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BIOCHEMICAL AND GENETIC ASPECTS OF

MENTAL RETARDATIONl
By JOHN H. MENKES, M.D. ,2 AND BARBARA RUBEN MIGEON, M.D.
The fohns Hopkins University School of Medicine, Baltimore, Maryland

INTRODUCTION
Mental retardation is a symptom common to a number of neurological
disorders of infancy and childhood. Its definition is ultimately a social one,
and implies a degree of intellectual malfunction incompatible with successful
social independence at maturity. In the majority of patients, retardation is
Annu. Rev. Med. 1966.17:407-430. Downloaded from www.annualreviews.org

detected in the early years of life, but in others, intellectual deterioration

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appears only after a variable period of normal development.

This review intends to summarize our knowledge regarding the disorders
which have mental retardation as a prominent clinical feature, and result
from a well-defined genetic defect. This may involve a single gene and, there­
fore, lead to an inborn enzymatic disorder or may be secondary to an anom­
alous chromosomal pattern.
In the first group of diseases, the diagnosis rests on the detection of a
biochemical abnormality, which may be the direct or indirect result of the
failure in enzymatic function. In the second group, microscopically evident
anomalies of chromosome structure confirm the diagnosis. It is perhaps a
significant commentary on the status of our knowledge concerning cerebral
functioning and intermediary metabolism that in none of these conditions
has it been possible to state either how the enzymatic defect produces men­
tal retardation, or to define unequivocally an abnormality in any one of the
numerous enzymes whose production must be controlled by genes located on.
the anomalous chromosome.

METABOLIC DISORDERS ASSOCIATED

WITH MENTAL RETARDATION
Over the last ten years, the number of metabolic disorders found to be
associated with mental retardation has increased strikingly. Even 50, these
conditions are still relatively uncommon and constitute 1 per cent or less of
the population within institutions for the retarded. In some of the more re­
cently discovered metabolic disorders, the association of a neurologic dis­
turbance may actually be fortuitous and merely the result of subjecting re­
tarded children, a highly selected group of individuals, to biochemical ex­
amination.
For practical purposes, the metabolic disorders will be divided into three
groups: Disorders of Amino Acid Metabolism; Disorders of Carbohydrate
1 The survey of the literature pertaining to this review was concluded in August
1965.
I Joseph P. Kennedy, Jr., Memorial Scholar in Mental Retardation.

407
 408 MENKES & MIGEON
Metabolism; and the Sphingolipidoses. The various metabolic defects which
have been associated with neurologic abnormalities are summarized in Ta­
bles I-III.
DISORDERS OF AMINO ACID METABOLISM

Phenylketonuria.-Phenylketonuria is an inborn error of amino acid

metabolism manifested by the inability of the body to convert phenylalanine
to tyrosine, and producing a clinical picture highlighted by mental retarda­
tion, seizures, and imperfect hair pigmentation.
Since its first description by Foelling in 1934 (1), the disease has been
detected in all areas of the globe. It is transmitted genetically as an autoso­
mal recessive, and its incidence in the general population of the United
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States, as determined from recently instituted mass screening programs, is

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approximately one in 10,000 (2). The condition is rarely observed among

Negroes and Jews of European descent (3). The enzyme defect in phenylke­
tonuria has been localized to the heat-labile fraction of phenylalanine
hydroxylase (4-8).
Phenylketonuric children are born with only slightly elevated phenylala­
nine blood levels, but upon protein ingestion, the amino acid accumulates in
serum and cerebrospinal fluid and is excreted in l arge quantities. In place of
the normal degradation to tyrosine, phenylalanine is converted to phenyl­
pyruvic-, phenyllactic-, and phenylacetic acid. In the newborn infant, the
transamination of phenylalanine to phenylpyruvic acid may not function,
and the keto acid will appear in the urine only between 2 and 34 days of age.
Since"a positive ferric chloride test is contingent upon the presence of this
metabolite, the reagent is inadequate for the early detection of the disease
(9).
In addition to the disruption of phenylalanine metabolism, tryptophan
and tyrosine are also handled abnormally (10, 11). The excretion of large
amounts of indole metabolites, and the reduced serum level of 5-hydroxytryp­
tamine (serotonin) are probably due to a partial inhibition of tryptophan
metabolism at different sites by the presence of large amounts of phenylala­
nine derivatives (12). A similar interference with the oxidation of tyrosine to
dihydroxyphenylalanine (DOPA), a melanin precursor, is probably responsi­
'
ble for the partial pigmentary defect of phenylketonuric children (13).
Alterations in the brain include mUltiple areas of defective myelination
(14), and a reduction in pigment content in the substantia nigra and locus
caeruleus (15).
Phenylketonuric infants appear normal at birth. During the first two
months of life vomiting and irritability may frequently be observed. By
four to nine months, delayed intellectual development becomes apparent
(16). In the untreated child, mental retardation is usually severe, and sei­
zures are common. The typical child is blond and blue-eyed with a rough,
dry, and often eczematous skin. A peculiar, musty odor, attributed to
phenylacetic acid, accompanies the patient, and may suggest the diagnosis.
 ASPECTS OF MENTAL RETARDATION 409
Significant neurologic abnormalities are rare. A variety of electroencephalo­
graphic disturbances have been found, but hypsarrhythmic patterns are
characteristic, even in the absence of seizures (17) .
The manner in which the defect in phenylalanine hydroxylase produces
mental retardation is unknown. Phenylalanine and its metabolites inhibit a
number of potentially vital enzymatic reactions (18, 19), and impair the
transport of amino acids into the brain (20) . However, it is clear that the
cerebral defect, once fully developed, is irreversible, and must therefore be
due to a permanent structural alteration of the brain. In some instances, a
decrease in white matter lipids and cerebrosides has been documented (21,
22) .
The diagnosis of phenylketonuria rests on the clinical features, the eleva­
Annu. Rev. Med. 1966.17:407-430. Downloaded from www.annualreviews.org

tion of blood phenylalanine, and finally, the presence of phenylpyruvic acid

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in urine.
It should, however, be emphasized that an increase in serum phenyl­
alanine during the neonatal period does not by itself assure the diagnosis of
phenylketonuria. While in the absence of adequately controlled studies a
restriction of phenylalanine intake is probably still advisable, a brief rein­
stitution of a normal diet during the first year of life is required to confirm
the diagnosis. The rapid rise in blood phenylalanine on a normal amino acid
intake, and the excretion of phenylpyruvate will be observed in a phenylke­
tonuric individual. Adult heterozygotes have normal fasting phenylalanine
levels but a somewhat reduced phenylalanine tolerance. Heterozygote
mothers may have abnormally high phenylalanine blood levels during the
latter part of pregnancy. Whether this contributes to the brain damage of
their homozygous mutant offspring is still uncertain (23, 24) . The problems
inherent in dietary management of phenylketonurics have been reviewed by
Centerwall, and by a British Conference Committee (25) .
Under treatment the electroencephalogram tends to revert to normal,
and abnormally blond hair regains its natural color. The effects on mental
development are, unfortunately, not as clear. While some data (26) would
indicate that early treatment is essential for the development of normal in­
tellect, we must emphasize that untreated phenylketonuria is not invariably
accompanied by mental retardation, and that dietary therapy, even when
instituted during the first week of life and maintained faithfully, does not
invariably prevent mental retardation (27) . At present, there is no informa­
tion as to the required duration of low phenylalanine intake, although re­
sumption of a normal diet at about four years of age did not produce mental
deterioration (28) .
Maple syrup disease.-This condition is a familial cerebral degenerative
disease due to a defect in oxidative decarboxylation of the branched-chain
keto acids, and marked by the passage of urine with a sweet, maple syrup­
like odor. The condition was first described in 1954 by Menkes et al. (29) . It
is transmitted as an autosomal recessive.
As a result of the failure in oxidative decarboxylation, the keto acid
 410 MENKES & .MIGEON
analogues of leucine, isoleucine, and valine are excreted in large quantities,
and the plasma concentrations of these amino acids are strikingly elevated
(30, 31) . Pathologic abnormalities in the nervous system are minor and
limited to a slight decrease in myelin deposition (32) . Chemical analyses
have, however, failed to show a decrease in concentration of the myelin
lipids, or any abnormalities in their structure (33) . The clinical picture in
most instances is marked by progressive decerebration, becoming nearly
complete by one month of age and leading to death. About half the affected
children develop severe hypoglycemia. The diagnosis rests on the character­
istic odor of the patient, and the presence of positive dinitrophenylhydrazine
and ferric chloride tests. A diet containing minimal amounts of leucine,
isoleucine, and valine has been used in treatment and apparently allows pa­
Annu. Rev. Med. 1966.17:407-430. Downloaded from www.annualreviews.org

tients to survive and achieve fair intellectual development (34) .

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Defects in urea cycle metabolism.-Three conditions, all extremely rare,

are known to result from blocks in the urea cycle. In all of these entities,
blood ammonia concentration is elevated; however, for obscure reasons, no
impairment in the production of urea has been noted.
Argininosuccinic aciduria, first described by Allan and others in 1958
(35) , is marked by mental retardation, poorly formed hair, and an accumu­
lation of the dipeptide argininosuccinic acid in body fluids (36) . It is marked
by a defect in argininosuccinase, and the metabolic block is at the site of the
conversion of argininosuccinic acid to arginine and fumaric acid (37) .
Citrullinuria, which probably is associated with a block in the conver­
sion of citrulline to argininosuccinic acid, has been seen in a mentally de­
fective patient (38), while a defect in ornithine transcarbamylase has been
documented in a family with congenital ammonia intoxication (39).
Histidinemia.-This condition, which may represent a harmless meta­
bolic variant, was first described by Ghadimi et al. in 1961, and in the ma­
jority of instances has been associated with mild mental retardation and
impaired speech development (40). A deficiency in histidase activity has
been noted in skin from affected individuals (41) . A positive ferric chloride
test in the absence of elevated blood phenylalanine suggests the diagnosis.
Homocystinuria.-Although this disease was only discovered in 1962
(42) , its frequency as a biochemical cause for mental retardation appears to
be second only to phenylketonuria. The clinical features include mental re­
tardation, ectopia lentis, cerebral and extracerebral thromboses, and fine
sparse hair (43) . A defect in hepatic cystathionine synthetase has been
noted (44) . The diagnosis of the condition may be made by a positive cyanide­
nitroprusside test (45).
The number of other, much rarer, inborn errors of amino acid metabolism
which have been associated with mental retardation is great, and these have
been summarized in Table I.
DISORDERS OF CARBOHYDRATE METABOLISM

Galactosemia Although galactosemia was first described in 1908 (57) ,

.-

the biochemical basis for the disorder was only uncovered in 1956 when
 ASPECTS OF MENTAL RETARDATION 411
Kalckar and Isselbacher were able to demonstrate a deficiency of galactose-
1-phosphate uridyl transferase, the enzyme catalyzing the conversion of
galactose-1-phosphate into galactose uridine diphosphate (58, 59) . The dis­
ease is transmitted as an autosomal recessive, and transferase activity in
parents of gal actosemic infants is but 64 per cent of normal (60) . An asymp­
tomatic variant of galactosemia in which homozygotes have partial trans­
ferase activity has recently been discovered (61) . In the untreated case,
pathologic lesions include pseudolobular hepatic cirrhosis (62) and a de­
creased amount of myelin (63) .
Since galactose metabolism is blocked at a point subsequent to phosphory­
lation of the sugar, galactose-1-phosphate accumulates in tissues, particu­
l arly erythrocytes, l ens, liver, and kidney. Blood galactose is elevated, and
Annu. Rev. Med. 1966.17:407-430. Downloaded from www.annualreviews.org

the excretion of the sugar is usuall y also increased. Galactitol, a reduction

product of galactose, may be detected in urine and brain (64, 65) .
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Galactosemic infants appear normal at birth, but in severe cases develop

symptoms during the first week of life. These include vomiting, diarrhea,
l istlessness, jaundice, and a failure to gain weight. By two weeks, hepato­
spl enomegaly and l enticular opacifications are detectable. Mental retarda­
tion is not consistently observed, and when present is never as marked as in
most phenylketonuric individuals (66) . The mechanism by which brain
damage is produced is obscure, although hypogl ycemia attending the inges­
tion of galactose, or the inhibition of phosphoglucomutase activity by
galactose (67) , may be responsible. In some infants, the disease will become
manifest only at a later age through the appearance of mental and physical
retardation. Asymptomatic homozygotes have also been detected (68) . The
presence of one or more accessory pathways for the metabolism of galactose
may account for this phenomenon (68, 69, 70) .
The diagnosis of galactosemia can be suspected from the presence of a
urinary reducing sugar, although galactosuria, often in combination with
glucosuria and fructosuria, may be seen in hepatic or renal tubular disorders
(71) . Proteinuria and aminoaciduria are also noted in the majority of cases
(72) .
Aside from a galactose tolerance test, which may produce severe hypo­
glycemia, the diagnosis can be confirmed by measuring either the accumu­
lation of galactose-1-phosphate when gal actosemic erythrocytes are incu­
bated with galactose (73) , the rate of (1_C14) galactose oxidation of C1402 by
whole blood, white cells, or helJlolysates (74) , or erythrocyte transferase ac­
tivity (75) .
Treatment by withdrawal of milk, and substitution of lactose-free pro­
tein products will result in all eviating gastrointestinal symptoms, and may
allow l iver function to return to normal. Cataracts may be reversibl e by
therapy, but the effect on intellectual development is uncertain (76) .
Gargoylism.-A syndrome of mental and physical retardation, multiple
skeletal deformities, hepatosplenomegaly, and congenital clouding of the
cornea was first described by Hunter in 1917 (77) , and later by H urler and
Pfaundler in 1919 (78) . At the present time, at least five different variants
 TABLE I �
-
N
DEFECTS IN AMINO ACID METABOLISM ASSOCIATED WITH NEUROLOGIC SYMPTOMS
Annu. Rev. Med. 1966.17:407-430. Downloaded from www.annualreviews.org

Clinical Features Accompanying

Disease Enzymatic Defect Biochemical Findings
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Mental Retardation

Phenylketonuria Phenylalanine Seizures, eczema, unusual odor. Hetero­ Increased blood phenylalanine (PA). In­
(1-28) hydroxylase zygotes have impaired phenylalanine toler­ creased urine PA, phenylpyruvate, o-hydroxy­
ance. phenylacetic acid. Ferric chloride--emerald
color.
�
Maple Syrup Oxidative decarboxy­ Decerebrate rigidity, seizures, hypogly­ Increased urinary branched-chain keto acids. t'rl
disease lation of branched­ cemia. Maple syrup odor to body and Increased serum branched-chain amino acids �
(29-34) chain keto acids urine. Leukocytes of heterozygotes have (leucine, valine, isoleucine).
�
impaired branched-chain keto acid oxidase Ferric chloride-navy blue color.
R>
activity (149)
�
Argininosuccinic
aciduria (35-37)
Argininosuccinase Seizures, white brittle hair (trichorrhexis
nodosa).
Elevated urine, spinal fluid argininosuccinic
acid. �
Z
Citrullinuria Impaired citrulline None Elevated blood, urine citrulline. Elevated
(38) utilization blood ammonia after high protein meal.

Hyperammo­ Ornithine transcarba­ Intermittent coma Elevated blood ammonia

nemia (39) mylase

Histidinemia Histidase Speech defect, but also in normals, Het­ Elevated serum histidine, urine imidazole
(40,41) erozygotes have reduced formiminoglu­ pyruvic, -lactic, and -acetic acid. Ferric
glutamic acid excretion after histidine chloride--emerald color.
load.
 Clinical Features Accompanying
Disease Enzymatic defect Biochemical findings
mental retardation

Homocystinuria Cystathionine Dislocated lenses. Vascular thromboses. Elevated plasma methionine, plasma and
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(42-45) synthetase Mottled skin, friable hair. urine homocystine. Nitroprusside test positive
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on urine.

·Cystathioninuria Cystathioninase Retardation in some, but others normal. Urine, brain cystathionine elevated.
(46,47)
1;;
""0
tTl
Hyperglycinemia
. Unknown Early ketosis,precipitated by protein in- Elevated blood glycine. Severe ketosis after �
(48) take, progressive extrapyramidal signs. leucine load. Unusual ketone bodies.
�'"!j
Hyperprolinemia A. Proline oxidase Renal hypoplasia,deafness, seizures. Elevated plasma, urine proline. �
(49) tTl
Z
B. Pyrroline-5-car­ Seizures �
t""'
boxylate dehydro­

�
genase (50)

Lysine intoler- Unknown Intermittent coma, spasticity. Increased plasma lysine and arginine, in­ :;0
ance (51) creased blood ammonia. t1
�
Hyperlysinemia Unknown Hypotonia and seizures, but also in nor­ Increased plasma and urinary lysine. (3
mal child. Z
(52,53)

Hypervalinemia Unknown Vomiting, failure to thrive, nystagmus. Increased serum, urine valine, negative ferric
(54) chloride.

Hartnup's Transport of Intermittent ataxia, rash, photophobia, Increased output of amino acids, indoIic com­
disease (55,56) neutral amino acids intellectual disturbances, no mental reo pounds. Intestinal transport of tryptophan t
tardation. impaired. W
 414 MENKES & MIGEON

have been recognized (Table II) . The principal biochemical disturbance in

all forms involves the metabolism of mucopolysaccharides (79). While
chondroitin sulfate A is the principal mucopolysaccharide of normal urine
(80), in the most common variant, the autosomal recessive condition and in
the rarer sex-linked recessive form, the mucopolysaccharide output con­
sists of chondroitin sulfate B and heparitin sulfate (81, 82). The pathological
alterations are widespread and involve almost every organ (83, 84). Large
vacuolated cells containing mucopolysaccharides may be found in cartilage,
tendons, periosteum, endocardium, and vascular walls. Another cell type,
containing a glycolipid, has been identified in the mitral valve (85). Muco­
polysaccharides accumulate in the lysosomes of most hepatic parenchymal
cells (86). In brain, the storage material includes both mucopolysaccharides
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and gangliosides (87, 88). Neurons in many areas of the neuraxis, particularly
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in the cerebral cortex, are swollen, and their nuclei are displaced peripherally
(89). In white matter, the perivascular spaces may be distended and filled
with aggregates of fat-laden cells. The leptomeninges are often fibrosed,
leading to an obstruction of the subarachnoid space and hydrocephalus (90).
The clinical picture of the two most common types of gargoylism varies
considerably in time of appearance, mode of expression, and rate of progres­
sion (91). X-ray a�normalities are quite extensive and have been reviewed
by Caffey (92).
Three other, relatively rarer, variants have been summarized in Table
II (81, 93, 94, 95). Pseudo-Hurler's disease, which clinically resembles the
autosomal form of gargoylism, is however, not accompanied by increased
mucopolysaccharide excretion, and has recently been shown to be due to
storage of a ganglioside (Table III) .
Several other rare defects in carbohydrate metabolism are accompanied
by intellectual retardation. These include fructose intolerance (96, 97), the
generalized (Type II) form of glycogen storage disease (98-101), dissemi­
nated lipogranulomatosis (102, 103), and lactic acidemia (104). (Table II) .
SPHINGOLIPIDOSES

Under this category we will group a number of hereditary diseases,

transmitted in an autosomal recessive manner, characterized by the deposi­
tion of abnormal quantities of sphingolipids within the nervous system, and
assuming a progressive course, variable only in time of onset, and rate of in­
tellectual and visual deterioration. Fairly up to date reviews of the chemistry
of these tomplex lipids have been compiled by Hanahan & Thompson (105)
and Svennerholm (106). These conditions may be subdivided according to
the nature of the storage material (Table III) .
Probably the most common of the entities is Tay-Sachs disease. In this
disease, the pathologic changes are confined to" the nervous system. Termi­
nally, almost every neuron in the cortex is swollen and its cytoplasm filled
with glycolipid material. On electron microscopic examination the lipid is
found to be arranged in concentric lamellae, about 25 A wide, and separated
 ASPECTS OF MENTAL RETARDATION 415
by a light zone of about the same width (107). Chemical examination indi­
cates an increase in ganglioside content, and on chromatography the pre­
dominance of a monosialoganglioside can be demonstrated (Table III)
(108).
Tay-Sachs disease occurs about fifty times more frequently in Jewish
than in non-Jewish families (109). For the first 3 to 10 months following
birth, infants appear normal. Lisdessness and irritability then appear, fol­
lowed by a loss of acquired abilities. A cherry-red spot in both macular areas
is invariable by the time neurologic symptoms are noted. The liver and spleen
are not enlarged. The disease progresses rapidly to a terminal stage of com­
plete blindness and loss of voluntary movements. During the latter part of
the illness, seizures and macrocephaly are common (110) .
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The clinical picture, particularly the cherry-red spot, suggests the diag­
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nosis. For completely obscure reasons, serum fructose-I-phosphate aldolase

levels are reduced in patients and their parents (111). There is no known
effective treatment.
The late infantile form of amaurotic idiocy first described by Bielschow­
ski (112) is a rather rare variant, distinguishable from Tay-Sachs in its later
onset, and by the deposition of a disialoganglioside within affected grey
matter (113).
Juvenile amaurotic idiocy.-This condition, which is almost as common
as the infantile form, occurs only rarely among Jewish children. Mental and
physical development are normal for the first few years of life, but by five to
seven years of age, intellectual deterioration becomes obvious. Electroen­
cephalographic abnormalities may, however, precede the earliest hint of
neurologic disturbance (114). Visual acuity is decreased, and there is macu­
lar degeneration, with a defective light reflex and deposition of a fine brown
pigment within the retina. The electroretinogram is abnormal even during
the early stages of the disease in contrast to the generally normal electro­
retinogram of Tay-Sachs disease (115) .
While histochemical examination suggests the deposition of a ganglio­
side within the ballooned neurons, neither an increase, nor an abnormal dis­
tribution of gangliosides has been documented (116) .
One of the more common forms of lipid storage disease is Pseudo-Hurler's
disease, or familial neurovisceral lipidosis. The clinical picture of this condi­
tion is marked by hepatosplenomegaly, bony abnormalities which resemble
those seen in gargoylism, intellectual deterioration, and a retinal cherry-red
spot (117). Mucopolysaccharide excretion is not increased, and the material
stored in brain and viscera has been identified as a monosialoganglioside
(Table III) (118, 119) .
Gaucher's disease.-Involvement of the nervous system is seen only in
the rapidly progressive infantile variant (120-122) and in the extremely rare
juvenile form of Gaucher's disease.
In infantile Gaucher's disease, the onset of symptoms is noted at about
4 or 5 months of age with apathy and loss of intellectual achievements.
 �
.....
0\
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TABLE II
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DEFECTS IN CARBOHYDRATE METABOLISM ASSOCIATED WITH NEUROLOGIC SYMPTOMS

Disease Enzymatic Defect Clinical Findings Accompanying Mental Retardation Biochemical Findings

Galactosemia Galactose-!-P04- Failure to thrive,hepatomegaly,jaundice, cataracts, Increased urine galactose,Ami­

(57-76) uridyl transferase heterozygotes have decreased transferase activity noaciduria
Elevated brain galactitol
s::
Gargoylism Unknown defects of 1. Autosomal recessive form (most common): mental 1. Increased output chontroitin tTl
(77-95) mucopolysaccharide deterioration skeletal deformities, hepatospleno­ sulfate Band heparitin suI- �
metabolism megaly,corneal clouding. fate. tTl
CJJ

2 Sex-linked recessive: usually no corneal clouding, 2. Increased output chondroitin Ro

longer life expectancy. B and heparitin sulfate. �
o
3. "Atypical"-intellectual deterioration, hepatomeg­ 3. Heparitin sulfate increased in tl
aly,normal bones (81). urine. Z

4 . "Adult form"-dwarfism, bony abnormalities, no 4. "Abnormal" chondroitin sui-

intellectual retardation,corneal opacities. fate B found in urine.

5. Morquio's disease (93, 94) (impaired growth, bony 5. Keratosulfate found in urine.
abnormalities,corneal clouding).

6. "Pseudohurler's"-see lipid storage diseases.

Annu. Rev. Med. 1966.17:407-430. Downloaded from www.annualreviews.org

Disease Enzymatic Defect Clinical Findings Accompanying Mental Retardation Biochemical Findings »
Ul
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'"0
Fructose Fructose-1-phosphate Failure to thrive, hypoglycemia. Increased urine fructose, amino- �
intolerance aldolase aciduria. til
(96, 97) o
"rj
Glycogen storage Alpha-glucosidase Muscular weakness, irrJpaired Decreased maltose cleaving ac­ s:::
disease (Type I I) ures, intellectual deterioration. tivity in leukocytes.
tTl
Z
( 98-101)
�
t""
Disseminated Irritability, hoarse cry, nodules over sites of trauma. Storage of mucopolysaccharides :;:0
lipogranuloma­ in mesenchymal cells only. tTl
tosis (102, 103) �
:;:0
t:I
Lactic acidemia ?Defect in pyruvate Chronic acido3is, convulsions. Decreased pyruvate removal.
(104) and alpha-ketogluta­ Lactate infusion produces pro­
�
rate decarboxylation longed blood lactate rise.
o
z

.;..
-
-r
 "'"
,... .
TABLE III ao

SPIDNGOLIPlDOSES
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Material Stored Disease Structure of Stored Lipid Clinical Findings

Late infantile amaurotic Ceramide-Glu-Gal-Gal-Gal-NANA Intellectual, visual deterioration, onset at 2

idiocy (112, 113) ) ) years of age_
NANA NHAC

Pseudo-H urlers Ceramide-Glu-Gal-Gal-Gal Intellectual deterioration, hepatosplenomeg- �

(117-119) I I aly, bony abnormalities, cherry-red spot. t:r1
NANA NHAC Z
:-::

Tay-Sachs Ceramide-Glu-Gal-Gal NHAC Intellectual deterioration, blindness, spas­

�
r.:o
Gangliosides (107-111) I ticity, cherry-red spot.
�
and NANA
derivatives
Juvenile Gaucher's
(124-126)
Ceramide-Glu-Gal Intellectual deterioration, hepatosplenomeg­
aly.
�
Z

Infantile Gaucher's Ceramide-Glu Hepatosplenomegaly.

(120-123)

Juvenile amaurotic ?Increased storage of normal gang- Ataxia, intellectual deterioration, abnormal
(114-116) idiocy Iiosides electroretinogram.

Sphingomyelin Niemann-Pick Ceramide-Phosphorylcholine Hepatosplenomegaly, intellectual deteriora­

(127-132) tion, myoclonic seizures, cherry-red spot.
 Material Stored Disease Structure of Stored Lipid Clinical Findings
Annu. Rev. Med. 1966.17:407-430. Downloaded from www.annualreviews.org

Sulfatides Metachromatic Ceramide-Gal-S03H2 Intellectual deterioration, peripheral nerve

leukodystrophy involvement, metachromatic bodies in urine.
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(133-138)
>
Ceramide Fabry's disease Ceramide-Glu-Gal-Gal Premature cerebrovascular accidents, punc- �
trihexoside (139,140) tate rash about lips and genitalia. Renal �
failure.
fA
Cephalin Cephalin lipidosis
o
Phospnatidyl ethanolamine Splenomegaly, intellectual deterioration "<j
(141) starting at 1-2 years of age.
�
tr:I
Fatty acid Refsum disease 3,7,11,15- Tetramethyl hexadecanoic Pigmentary degeneration of retina, ataxia, Z
(142, 143) acid chronic polyneuritis, ichthyosis, increased �
t""
CSF protein.

fg
Lipid-carbohydrate­ Infantile neuroaxonal Mental retardation, hypotonia.
protein complex dystrophy
?
�
:;c

�
(144)

Cholesterol Cere brotendinous Cholesterol Mental deficiency, cerebellar disease, myo- o

(145) xanthomatosis clonus. z

NANA=N-acetylneuraminic acid; Glu=glucose; Gal=galactose; Gal-NHAC=galactosamine; Ceramide=fatty acid amide of

sphingosine (CHa(CH2)14CH= CH-CHOH-CH-CH20H)
I
NHCOR
,j>.
.....
IQ
 420 MENKES & MIGEON

These are followed by opisthotonos, bulbar signs, and progressive spasticity.

Splenomegaly is quite marked, but neither liver nor lymph nodes may be
enlarged. Occasionally, retinal cherry-red spots are present. Changes in the
brain consist of minimal neuronal cytoplasmic accumulation of a glycolipid
and neuronal degeneration (122).
Juvenile Gaucher's Disease is differentiated from the infantile form by a
slower progress of cerebral symptoms, and pathologically by the striking
neuronal accumulation of glycolipids (123, 124) . In contrast to the ceramide
monohexoside (cerebroside) stored in the usual form of Gaucher's disease,
ceramide dihexoside (cytoside) appears to be the main glycolipid in viscera
and brain in this entity (121, 125, 126).
Niemann-Pick's disease.-This condition, first described by Niemann in
Annu. Rev. Med. 1966.17:407-430. Downloaded from www.annualreviews.org

1914 (127), is characterized by an accumulation of sphingomyelin in the

by North Carolina State University on 06/01/13. For personal use only.

reticuloendothelial system. Cerebral involvement is frequent but not invari­

able. The lipid is deposited in foam cells within a number of viscera, includ­
ing liver, spleen, lungs, and bone marrow. In the brain, neurons are swollen,
and the lipid material is stored within the cytoplasm, ultimately producing
neuronal degeneration. On chemical analysis, grey matter, and to a lesser
extent, white matter sphingomyelin, is elevated in patients who present
with cerebral involvement (128, 129). The increase involves the short-chain
(extramyelin) sphingomyelin molecules predominantly (130).
The disease is transmitted genetically as an autosomal recessive. The
onset of symptoms is variable, ranging from birth to six years of age. In one­
third of the patients, neurologic symptoms predominate during the early
stages of the disease. These consist of intellectual deterioration, seizures,
particularly myoclonic jerks, and spasticity. Retinal cherry-red spots are
found in 25 per cent of the patients, and may precede other neurologic ab­
normalities (131).
The presence of hepatosplenomegaly and anemia in children with intel­
lectual deterioration should suggest a diagnosis of Niemann-Pick's disease.
This can be confirmed by bone marrow aspiration or splenic biopsy. Atypi­
cal forms of the disease with a protracted clinical course have been docu­
mented (132).
Metachromatic leukodystrophy . Gr eenfield first called attention to this
-

condition in 1933, describing it as a form of diffuse sclerosis (133). Clinically,

it is a cerebral degenerative condition, differentiated from other similar en­
tities by the presence of peripheral neuritis, and the finding of metachroma­
tic bodies in urine (134, 135). The outstanding pathologic features are a dif­
fuse demyelination, and the accumulation of large quantities of metachro­
matically staining granules either free in cerebral tissues, or stored within
glial cells (136). From both histochemical and biochemical studies, it has
become evident that the granular material is lipid in nature, and represents a
sulfuric acid ester of cerebroside (137) (sulfatide). Sulfatase, an enzyme
normally active in brain, liver, and kidney, has been shown to be absent from
 ASPECTS OF MENTAL RETARDATION 421
liver and kidney of affected individuals (138). This enzyme is able to con­
vert sulfatides to cerebrosides, and may, therefore, be active in the turnover
of sul£atides within the nervous system.

OTHER METABOLIC DEFECTS ASSOCIATED

WITH MENTAL RETARDATION
A large number of other conditions, whose exact nature is still unclear
have, at one time or another, been associated with impaired cerebral func­
tion. In addition to the lipid storage diseases listed in Table III, the follow­
ing defects should be mentioned.
1. Hyperuricemia. Distinguished by mental retardation, choreoatheto­
sis. and marked self-destructive biting (146) .
Annu. Rev. Med. 1966.17:407-430. Downloaded from www.annualreviews.org

2. Acanthocytosis. Here, mental retardation is accompanied by a defect

by North Carolina State University on 06/01/13. For personal use only.

in beta-lipoprotein synthesis, and the presence of peripheral neuritis, pos­

terior column degeneration, and retinitis pigmentosa (147, 148) .
While the biochemical findings suggest a possible site for the metabolic
lesion in these diseases, a number of other neurologic conditions are known
in which there is even less evidence for the nature of the biochemical abnor­
mality. They include the grey and white matter degenerations, Hallervorden­
Spatz disease, and Unverricht's myoclonus epilepsy. Finally, in all of the
system degenerations, the hereditary nature of the illness points to an en­
zymatic lesion whose site is still completely obscure.
CHROMOSOMAL ANOMALIES

The most striking single clinical observation common to almost all the
individuals with chromosomal anomalies is impaired intellectual function.
This is not unexpected since rearrangement of genetic material to such a
degree as to be visible as altered chromosomal morphology must involve
numerous genetic loci, and interfere extensively with growth and differentia­
tion of the developing human zygote. Fraser-Roberts (150) estimates that
more than half of the normal variation in intelligence is transmitted geneti­
cally, and that the bulk of this heritable variation is multifactorial, that is,
determined by more than one gene pair. Mental retardation associated with
chromosomal aberrations is accompanied by either gross anatomical mal­
formations of the central nervous system or apparently normal morphology.
One cannot treat all reported instances of mental retardation associated
with chromosomal anomalies or describe the clinical and cytological findings
in the various cytogenetic syndromes. For this the reader is referred to several
excellent recent reviews of aberrations involving the autosomes (151, 152),
sex chromosomes (153) , and mongolism (154) . We will concern ourselves
with those aspects of chromosomal abnormalities pertinent to a discussion
of mental retardation.
Intellectual impairment is associated with various abnormalities of the
sex chromosomes and autosomes. These include reduplication such as
 422 MENKES & MIGEON

trisomy, partial trisomy, tetrasomy, and pentasomy, and deficiencies such

as deletions and monosomy X. As in the case for the aminoacidurias, the
incidence of mental defect in chromosomal abnormalities is difficult to as­
certain because of the strong bias in the sample of population surveyed for
chromosomal abnormalities. Many of the abnormal sex chromosome con­
stitutions have been ascertained by surveys of the institutionalized retarded,
using sex chromatin analysis as the screening device. Abnormalities of the
autosomes have been searched for almost exclusively in children with multi­
ple congenital anomalies and mental retardation. A better evaluation of the
relationship of abnormal sex chromosome composition to intellectual defect
has been obtained from results of sex chromatin surveys in a newborn popu­
lation or infertility clinics. Studies in other species as well as our own (1SS)
Annu. Rev. Med. 1966.17:407-430. Downloaded from www.annualreviews.org

have shown that large duplications or deficiencies in the autosomies are fre­
by North Carolina State University on 06/01/13. For personal use only.

quently lethal. If the organism survives, the effect of trisomy is usually

manifested by multiple severe congenital malformation so that the sampling
in the detection of autosomal trisomy may not be misleading. The association
of partial trisomy or small deletions with mental retardation, however, may
be fortuitous since studies in the normal population have revealed chromoso­
mal variants unrelated to obvious physical or intellectual defect (156, 157).
SEX CHROMOSOME ABNORMALITIES
As determined by buccal smear surveys in more than 25,000 newborns
(153) , the incidence of sex chromosome abnormalities is about 2.1 per 1000
for males and 1. 6 per 1000 for females. In the male, one third of the abnor­
malities are XXV or Klinefelter's syndrome. The great majority of the ab­
normalities in females involve the triple X syndrome (XXX) , with but one
fourth of the patients being X monosomies or variants thereof (Turner's
syndrome).
Surveys of male inmates in mental institutions (153) show a greater fre­
quency of abnormal sex chromatin patterns (8. 1/1000) than in the newborn
population reffecting the greater incidence of XXV males (5. 4/1000) in this
group. The frequency of XY /XXY mosaic males is approximately the same
in institutionalized retarded as it is in the newborn. Money (158) has shown,
using a selected small sample, that Klinefelter's syndrome is not invariably
associated with an intellectual deficit. The IQ in this group approximates
the normal curve rather closely and ranged from the grossest mental defect
to superior levels. About one fourth of the chromatin-positive males seen in
infertility clinics are retarded. The retardation associated with the XXV
karyotype is usually not severe, and these males may be institutionalized
because of psychoses and antisocial behavior.
Although all X chromosomes in the karyotype in excess of one are late
replicators (159) and at least partially inactivated (160) , the severity of the
intellectual defect seems to increase proportionately with the number of X
chromosomes in excess of normal.
The XXXV karyotype has always been associated with severe mental re­
tardation (161, 162) , distinguishing this variant phenotypically from the
 ASPECTS OF MENTAL RETARDATION 423

more common XXV male. The XXX/XV males show extreme mental de­
ficiency along with skeletal anomalies and gonadal dysplasia (163) .
The only apparently viable monosomy in man is that associated with
short stature and gonadal aplasia (Turner's syndrome). The absence of an
X chromosome usually does not carry with it any severe intellectual defect.
The incidence of Turner's syndrome is no greater among institutionally re­
tarded than in the newborn (0.3/1000) (153). The IQ closely follows the
normal curve (158, 164). Shaffer (164) has shown that this group of females
shows a discrepancy between verbal comprehension and perceptual organiza­
tion, which reflects a degree of dysgnosia for space-form perception that
pertains equally well to the chromatin-positive as to the chromatin-nega­
tive Turner's female.
Annu. Rev. Med. 1966.17:407-430. Downloaded from www.annualreviews.org

The presence in the female of more than two X chromosomes is usually

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detrimental. Although there is no definite clinical pattern in females with

XXX sex chromosome complement, the majority show mild mental re·
tardation and the frequency of this chromosomal pattern among institu­
tionalized retarded is about three times (4.3/1000) that seen in the normal
newborn (153). The tetrasomic X females (XXXX) reported by Carr et al.
(165) show normal sexual development but are mentally retarded.
The only reported X pentasomy (XXXXX) was in a two-year-old child
with a behavioral age of less than six months (166).
The human Y chromosome may show great variation in size (167), which
may be directly inherited (168) . The presence of more than one Y chromo­
some in the karyotype does not seem necessarily deterimental to the organism
although it may reflect a familial tendency to meiotic errors and be associated
with transmission of aneuploidy (169). There is no specific phenotype as­
sociated with the XYY chromosome constitution and the XYYY child re­
ported by Townes was only mildly retarded (IQ 80) (170). All of the twelve
XXXYY males reviewed by Schlegel (171), however, show an intellectual
defect with IQ range from 35-74.

AUTOSOMAL ABNORMALITIES
By far the most common and best defined autosomal anomaly is associ­
ated with mongolism. Because of the prevalence of case material the cyto­
genetics of mongolism have been fairly well worked out, and this condition
has served as a prototype for the kinds of aberrations and the genetic
transmission of other autosom'al abnormalities. The remarks which follow
therefore might also be appropriate for other autosomal trisomy syndromes,
especially in regard to mosaicism and genetic transmission.
Mongolism is associated with either an extra small acrocentric chromo­
some (172), probably #22,3 the smaller acrocentric pair (173), or an effective
trisomy for the G14 chromosome which involves translocation of that chro­
mosome to another chromosome usually in the 13-15 (D) or 21-22 (G)

3 Den ver classification (210).

4 According to the group nomenclature of Patau.
 424 MENKES & MIGEON

groups. One cannot distinguish clinically between mongols with "regular"

G trisomy from those with an effective trisomy translocation. The associa­
tion of mongols with normal karyotype has been reported in two instances
although mosaicism can never be completely excluded (174, 175).
The frequency of "regularly" trisomic mongols apparently increases with
maternal age as reflected by increased frequency of mongols in older mothers
(176) , while the translocation mongol occurs independently of maternal age.
The majority of translocations producing mongolism arise de novo in the af­
fected child and will not be associated with familial mongolism. Data ob­
tained from the study of 227 mongols of young mothers (177) (age 15 to 29
years) show 92 per cent "regular" trisomy to 8 per cent with translocation.
Of 18 translocation mongols, 13 involved a translocation between the G1
Annu. Rev. Med. 1966.17:407-430. Downloaded from www.annualreviews.org

chromosome and the D group, while five showed a translocation between

by North Carolina State University on 06/01/13. For personal use only.

two members of the G chromosome group. In only four of the translocation

mongols (all D/Gl) were the mothers carriers of the translocation (fre­
quency 0.018) so that the incidence of translocation carriers in the families
of mongols is low. There seems to be some selection operative in transmission
of DIG, translocations from paternal carriers, whose progeny are carriers or
normals, and rarely translocation mongols (178, 179).
Studies of the rare families in which there is more than one mongol have
shown a preponderance of "regularly" trisomic mongols without evidence of
mosaicism in the parents (180, 181). There may be a transmittable tendency
to meiotic errors in some of these families with multiple occurrence of
aneuploidy in sibships (182-184).
There is little correlation between the degr ee of physical stigmata and in­
telligence level in the mongol as demonstrated objectively for the palmar
ATD angle by Dunsdon (185). The mongol brain characteristically weighs
less than that of a normal individual of the same age and sex and has a par­
ticularly small cerebellum, flattened occipital contour, and poorly developed
superior temporal gyrus. The abnormalities of shape may well be attributa­
ble to the retarded skull growth (186). The intelligence quotients in mongols
(185) vary from an upper limit of 70 to under 25 with a mode of 40-44. Ex­
ceptional intelligence has usually been associated with atypical cytogenetic
findings inclu ding partial trisomy (187-189) or mosaicism (190-192).
M osa ici sm for the G1 tr isomy, however, has been described with a "forme
fruste" of mongolism (lo w grade mental deficiency) (193, 194) as well as in
phenotypically unremarkable mothers of typical trisomic mongols (195).
The level of intelligence is not well correlated with the precentage of diplo
Gl and triplo G1 cells in the blood.
How the presence of a small acrocentric chromosome in triplicate pro­
duces the mongol phenotype is still unknown. Numerous attempts to map
the G1 c hromos ome have been unsuccessful. Demonstrations of higher levels
of alkaline phosphat ase (196), galactose-I-phosphate uridyl transferase
(197), and glucose-6-phosphate dehydrogenase (198) (X chromosome­
determined) in the leukocytes of mo ngols have not been reproducible in
fibroblasts, and suggest that the increased leukocyte enzyme activity may
 ASPECTS OF MENTAL RETARDATION 425

represent a generalized disturbance of enzyme activity within that cell

(198). The recent demonstration (199) of decreased serotonin in the whole
blood of ten "regularly" trisomic mongols, and normal levels in seven trans­
location mongols similarly may not reflect the direct consequence of a
triple dose of the genes which specifically regulate serotonin activity.
Trisomy of an apparent group G chromosome in the absence of mongo­
lism has been reported (151) in males or mosaic females with a heterogenous
phenotype and some degree of mental retardation. Whether the additional
genetic material represents trisomy of a G2 chromosome, Y chromosome, or
partial trisomy of a larger chromosome is not deducible on the basis of
chromosomal morphology alone.
Even though most of the children with the multiple severe congenital
Annu. Rev. Med. 1966.17:407-430. Downloaded from www.annualreviews.org

malformations associated with the 13-15 (D1) (200) and 17-18 (E1) (201)
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trisomy syndromes do not survive infancy, mental retardation has been in­
ferred from the neurologic abnormalities detected during lifetime and the
severity of mental defect in survivors and in individuals with apparent par­
tial trisomies for the same chromosome groups. There is a severe malforma­
tion of the brain frequently associated with the Dl trisomy syndrome, in­
cluding incomplete cerebral development with failure of interhemispheric
cleavage, absence of the external olfactory apparatus, and an unusually
large number of heterotopic neurones in subcortical white matter (202).
The arrhinencephaly and sagittal cleft of facial structures may be secondary
to defective formation of the skull blastema. Absent olfactory apparatus
has been occasionally associated with the E1 trisomy syndrome (203), and
with a short arm deletion of a chromosome 17-18 (204). No consistent cen­
tral nervous system malformation is associated with the El trisomy syn­
drome, but spasticity is frequently observed. Deletions in the short arm of
the earlier replicating chromosome in the B group (205) have been associated
with microcephaly, a host of minor skeletal anomalies, growth failure,'
mental retardation, and transient kitten-like cry (206). It is interesting to
note that this same constellation of abnormalities (growth failure, micro­
cephaly, severe mental retardation, and minor skeletal anomalies) may ac­
company deletion of the short arm of chromosome 18 (181, 207, 208) and
may represent the result of small deletions of any chromosome. The produc­
tion of a specific symptom complex associated with abnormalities at mul­
tiple genetic loci has been demonstrated (the Minute reaction) for Drosophila
melanogaster (209).
In summary, gross chromosomal abnormalities are almost always asso­
ciated with some degree of intellectual defect, m�st marked in the autosomal
trisomies and partial monosomies, and in the tetrasomy and pentosomies of
X. The cause of the retardation is generally attributed to the loss or dupli­
cation of blocks of structural or regulatory genes concerned with the syn­
thesis of proteins essential to the normal development of the human organ­
ism. Specific elucidation of the biochemical basis for retardation has yet to
come.
 426 MENKES & MIGEON
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