TABLES OF CONTENTS

Tables of contents ....................................................................................... 1

List of tables ................................................................................................ 2
List of figures .............................................................................................. 3
Abstract ....................................................................................................... 4
Chapter I. Introduction ................................................................................ 5
Chapter II. Case report ................................................................................ 6
Chapter III. Literature review ..................................................................... 14
Chapter IV. Case analysis ........................................................................... 24
Chapter V. Summary ................................................................................... 27
References ................................................................................................... 28

1
 LIST OF TABLES

Table 1. Laboratory examination ................................................................ 11

2
 LIST OF FIGURES

Picture 1. Patient family pedigree ............................................................... 9

Picture 2. Picture of patient ......................................................................... 10
Picture 3. Picture of Head MRI.................................................................... 12

3
 ABSTRACT
Eleven-year Eight-month old girl with Metachromatic Leukodistrophy
Ahmad Ulil Azmi, Mexitalia Setiawati
Departement of Pediatrics, Medical Faculty of Diponegoro University
Dr.Kariadi Hospital Semarang

Background: A uncommon form of lysosomal storage disorder called

metachromatic leukodystrophy is brought on by insufficient arylsulfatase A
activity. It is inherited in an autosomal recessive manner. It is a serious condition
that, in its early-onset form, results in death within 5–6 years. Quick diagnosis and
treatment can improve one's quality of life. The origin, assessment, and
management of metachromatic leukodystrophy are discussed in this activity,
which also emphasizes the need of the interprofessional team in diagnosing and
treating individuals with this condition.
Case report: a 11-year-old girl with complaints seizures, seizures in all limbs, the
duration of the seizure was approximately 1 minute, the seizures stopped by
themselves, the child was conscious after the seizure. Seizures without fever, In
December 2019 the child could not walk at all, the child only fell asleep, his
hands and feet were stiff, sometimes he could sit up. The child also has no contact
with the parents, the seizures are still recurring. The child was referred to the
hospital. Kariadi for an MRI examination results, diagnosed with epilepsy and
suspected of having an inborn error in metabolism, The child is then consulted to
the nutrition and metabolic disease for diagnosis.
Conclusion: Metachromatic leukodystrophy is a rare lysosomal storage disease.
The incidence of JDM ranges from 1/40,000 to 1/100,000 children per year. In
Indonesia there is no data regarding the incidence of this disease.

4
 CHAPTER I
INTRODUCTION

An uncommon form of lysosomal storage disorder called metachromatic

leukodystrophy is brought on by insufficient arylsulfatase A activity. It is
inherited in an autosomal recessive manner. primarily impact the cellular
components and white matter tracts of the central nervous system (CNS). The
incidence of JDM ranges from 1/40,000 to 1/100,000 children per year. This case
report discusses 11-year 8-month-old girl with metachromatic leukodystrophy,
Patient had epilepsy, developmental regression, cognitive impairment, mental
deterioration, and motor delay with onset at the age of 11. The diagnosis with
anamnesis, physical examination and imaging MRI from brain. 1-2
Metachromatic leukodystrophy is a progressive disease. All physical and mental
abilities are finally lost due to this illness. The age of a person's initial diagnosis
frequently affects their life expectancy. Therapy is a symptomatic treatment, and
Genetic counselling.3
This case report discusses 11-year 8-month old girl diagnosed with
Metachromatic leukodistrophy who experience neurological disorders and its
management.

5
 CHAPTER II
CASE REPORT

2.1. PATIENTS DESCRIPTION

The patient inthis case was born on Februari 22, 2010. She is 11-year 8-month
right now, lives in Pati, with medical record number C795195. This girl with
suspect inborn error of metabolism, inpatients at Dr.Kariadi Hospital on Februari
22th, 2020.

2.2. HISTORY OF PRESENT ILLNESS

Chief complaint: Recurrent seizure
± since the age of 8 years the child has complained that when he walks he
suddenly falls, falls and sometimes hits his head, the child has not complained of
headaches before, he denies pain in both legs. The child also begins to behave
strangely, sometimes laughing, crying or getting angry for no reason, if someone
is nearby the child tends to hit the person often. Parents take their children to see a
doctor at the Puskesmas, then they are advised to go to a hospital in Pati.
However, parents only take their children for treatment to the village shaman. 4
months after the first complaint the child started having seizures, seizures in all
limbs, the duration of the seizure was approximately 1 minute, the seizures
stopped by themselves, the child realized after the seizure. Seizures without fever.
The mother did not take the child for treatment, repeated seizures in 1 week 3
seizures with the same type and pattern. The longer the seizures, the more
frequent, almost every day the child has seizures with seizures lasting up to 5-10
minutes. The child was then taken to the hospital for treatment. Starch. A CT scan
was performed, but it was said that there were no abnormalities. It is
recommended to be referred to the hospital. Kariadi, but parents do not want. The
child received anti-seizure drugs, piracetam, phenytoin and valproic acid.
Children routinely control to the hospital. Starch to get anti-seizure drugs, but
complaints of seizures do not improve.

6
In May 2019 the child was referred to the hospital. Telogorejo for EEG, obtained
the impression of visible epileptiform waves, with ictal EEG spikes, slow spike
waves. Children still have complaints of recurrent seizures almost every day.
Children are advised to go to the hospital. Kariadi but parents refused. In
December 2019 the child could not walk at all, the child only fell asleep, his
hands and feet were stiff, sometimes he could sit up. The child also has no contact
with the parents, the seizures are still recurring. The child was referred to the
hospital. Kariadi for an MRI examination, and just received an MRI schedule for
February 2020. February 2020 the control child went to the hospital's neurology
polyclinic. Kariadi with MRI results, diagnosed with epilepsy and suspected of
having an inborn error in metabolism, received anti-epileptic kepra and valproic
acid. The child is then consulted to the nutrition and metabolic disease polyclinic
for diagnosis. Children are programmed to be hospitalized via TPPRI.

PAST MEDICAL HISTORY

- At the age of 8 months, the child complained that the right limb was not as
active as the left limb, the right hand gripped more often
- At the age of 4, the child's big toe was amputated because it was pinched by the
spokes of a bicycle, since then, according to the parents, the child's right foot is
smaller than the left foot
- The child stays in class during grade 1, because he cannot attend school lessons
- Diagnosed with epilepsy since the age of 8 years

2.4. FAMILY MEDICAL HISTORY

There is no family history with same illness.

PERINATAL HISTORY
Patient was born from G2P2A0, 24-year-old mother, aterm pregnancy, per
vaginam delivery, birth weight 2.100 grams, birth length 489 cm, crying
immediately. History of illness during pregnancy denied. ANC >4x at obstetrician
and midwife.

7
FEEDING HISTORY
Patient received breast milk since birth until 8 months old. At 6-month old patient
got some porridge, at 8 month old porridge and formula milk SGM. At 1 years old
patient ate family food.

ANTHROPOMETRY
Body weight : 19.6 kg
Body length : 133 cm
Ideal body weight : 32 kg
WAZ : NA
HAZ : -2.33 SD
BMI : -4.66 SD
Impression : Severe chronic malnutrition
DEVELOPMENTAL HISTORY
Mother said New children can sit at 8 months, walk at 18 monthsSpeaking at the
age of 2 years, only last words like num, right, di, 3 years old speak words, 4.5
years old speak 2 words (mama eats).
At the age of 6 years, children go to public elementary schools, but the children
cannot attend lessons, so the children stay in class. Children can write aaa, bbb,
but can't read yet. 7 year old child is still in elementary school class 1, writing like
grass can't be read. Children do not continue school because children often have
seizures when they are 8 years old.

PEDIGREE

8
 Picture 1. Patient family pedigree

2.3. PHYSICAL EXAMINATION

On February 24th 2020, apatis, vital signs show blood pressure 90/60 mmHg,
heart rate 88 bpm, respiratory rate 18 breaths/minute, temperature 36,4 0C, oxygen
saturation 99% room air, regular and adequate pulse. Body weight 19.6 kg, body
length 133 cm, WAZ NA, HAZ -2.33 SD, BMI -4.66 SD. pupils were equal,
round and decrease reactive to lights, with diameter 4 mm/4mm, no conjunctiva
anemic, no palpebra edema. Ears were clear, no discharge. There was no nasal
flaring, no nasal discharge. Mouth mucous membrane was moist, no cyanosis.
Neck examination revealed no lymphadenopathy. Chest expansion was
symmetrical and no retraction was visible. Heart sounds were normal, with no
murmur or gallop. On lungs auscultation, basic sound vesicular was normal, no
crackles, no rhales, no wheezes. Abdomen was soft, flat, liver and spleen were not
palpable, skin turgor returned quickly. Extremities were warm, no cyanosis, no
edema, capillary refill less than 2 seconds, muscle wasting (+), increase on
physiological reflexes in fourth extremities, no pathological reflexes, spastik (+).

9
Picture 2. Picture of patient

10
 Table 1. Laboratory examination

Normal Unit 22/02/2020

range
Hb 11,8 – 15,0 g/dL 13.3
Ht 32 – 62 % 40.3
Erytrocite 3,1 – 5,4 106/uL 4.57
MCH 24 – 30 pg 29.1
MCV 77 – 95 fL 88.2
MCHC 29 – 36 g/dL 33
Leucocytes 5 – 13,5 103/uL 7.900
Platelets 150 – 400 103/uL 186.000
RDW 11,6 – 14,8 % 13
Ureum 15 - 39 g/dL 15
Creatinin 0.6 – 1.7 Mg/dL 0.7
Sodium 136 – 145 mmol/L 145
Pottasium 3,5 – 5,0 mmol/L 4.2
Chloride 95 – 105 mmol/L 112
Lactat 0.4 – 2.0 mmol/L 2.42
BGA 22/2/20
pH 7.42
PCO2 33.4 mmHg
PO2 102.3 mmHg
FiO2 21%
HCO3- 22.7 mmol/L
TCO2 23.7 mmol/L
Becf -2.0mmol/L
BE (B) -0.6 mmol/L
SO2c 98.1%
A-aDO2 8.6 mmHg

11
Picture 3. Picture of Head MRI

12
Head MRI without contrast (17/02/2020)
- Hiperintens lesion T2WI dan T2FLAIR in frontal area, temporal, and right and
left parietal white matter (Dominant in frontal area white matter)
- Ventriculomegaly with atrophy parenkim cerebri and cerebelli
 Tend to be an image inborn error metabolism, still possible leukodystrophy dd/
metachromatic leukodystrophy, alexander disease
- No visible infark, hemorraghic, or SOL intracranial

ASSESMENT
- Severe chronic malnutrition
- Suspect Inborn error metabolisme
- Epilepsi General on terapi

MANAGEMENT
- Valproic acid 5,5 ml/8 hours
- Kepra 1 tablet/12 hours
- Laktulosa syrup 10 ml/8 hours

13
 CHAPTER III
LITERATURE REVIEW

3.1. METACHROMATIC LEUKODYSTROPHY

3.1.1. DEFINITION AND EPIDEMIOLOGY
Metachromatic leukodystrophy is a autosomal recessive lysosomal storage
disease caused by a functional deficiency of the lysosomal enzyme arylsul- fatase
A( ASA or ARSA). ASA deficiency leads to the accumulation of sulfatides in the
central and peripheral nervous systems, which is associated with demyelination
and consequent neurodegeneration. Patients with MLD generally experience
progressive loss of gross and fine motor functions and a severe decline in
cognitive function, ultimately leading to premature death. The prevalence of
metachromatic leukodystrophy in northern European and North American
populations ranges from 1 atau 40, 000 to 1 atau 100, 000. In the United States of
America, the incidence is thought to be 1 atau 40, 000 of births. There are nomor
racial or sexual preferences. Based on the age of onset, the disease is divided into
categories. On the prevalence of JDM in Indonesia, there is nomor information..2

3.1.2. ETIOLOGY AND PATHOGENESIS

A collection of inherited conditions known as lysosomal storage diseases

(LSDs) affect the lysosomes, specifically the enzymes that are involved in cell
metabolism, signaling, substrate processing, innate immunity, apoptosis, and other
intricate cell recycling processes. This procedure is really intricate. The host cell
becomes toxic as a result of an accumulation of unprocessed or incompletely
processed chemicals. Most diseases start in early infancy or childhood, however
others start in maturity. LSDs can result in multi-organ failure, mortality, and a
neurodegenerative course that progresses over time.2

14
 MLD is caused by the deficiency of arylsulfatase A lysosomal
enzyme( ARSA) and sphingolipid activator protein B( SapB or saposin B) as a
consequence of mutations in the ARSA and PSAP genes, respectively, ARSA
deficiency cannot be compensated by other enzymes. The ARSA gene is located
on chromosome 22q13. 33 and consists of 9 exons. ARSA is synthesized as a pre-
protein, then the signal peptide is cleaved in the EPR, resulting in the formation of
a mature ARSA protein consisting of 489 amino acids with a molecular weight of
51, 908 Da. For all lysosomal enzymes, including ARSA, lysosome targeting is
ensured by the presence of mannose 6- phosphate( M6P) residues, which are
added to the lysosomal enzymes as it passes through the Golgi complex( GC).
After entering the lysosome, the M6P is cleaved off the enzyme. 3- 4 At
lysosomal acidic pH, ARSA exists as a homo- octamer composed of 4 dimers
arranged in a ring- like structure. However, it is predominantly dimeric at neutral
pH. The physiological substrate of ARSA is sulfatide( 3- O- sulfo-
galactosylceramide, cerebroside- 3- sulfate, galactosyl- 3- sulfate ceramide). 5

The white matter tracts and cellular components of the central nervous
system( CNS) are the primary targets of leukodystrophies, which are hereditary
diseases. Glial cells, myelin sheaths, and axons are examples of these. An inborn
metabolic mistake in the lysosomal enzyme arylsulfatase A results in
metachromatic leukodystrophy, an autosomal recessive hereditary leukodystrophy
and LSD.. Sulfatides build up as a result, which causes the CNS/PNS myelin
sheaths to malfunction and eventually die. It also builds up in the kidneys, testes,
and gallbladder, among other organs. Based on the disease's clinical
characteristics and age of start, it can be categorized. Neurodevelopment and
neurocognitive performance progressively deteriorate in all illness kinds.6

Arylsulfatase A is inactive, which leads to metachromatic leukodystrophy.

Arylsulfatase A (ARSA) gene mutations are almost always found on chromosome
22q13. 3- qter. A and I, two alleles that have contributed to about 50% of
instances and are in charge of the various clinical manifestations of the illness. 4
In some instances, it is brought on by a lack of the sphingolipid activator protein

15
SAP-B (saposin B), which is in charge of causing ARSA to degrade sulfatides.
Prosaposin gene mutations are the cause of this type (PSAP gene).7,9

 METABOLIC DERANGEMENT
The primary metabolic defect is a block in lysosomal degradation of sulfatide( or
galactosylceramide- sulfate) and other sulfated glycolipids In vivo, the sulfatide is
presented to the enzyme arylsulfatase A( ASA) as a 1: 1 complex with sap- B. A
deficiency of either ASA or sap- B can cause MLD. Few cases with sap- B
deficiency have been documented, most with a late infantile form. Sulfatide is a
prominent lipid component of the myelin sheath. Its ratio to galactocerebroside
plays a role in the stability and physiological properties of this membrane.
Progressive accumulation of sulfatides( and likely lysosulfatide) in the central and
peripheral nervous system will soon lead to disruption of the newly formed
myelin and intense demyelination. In MLD, sulfatide also accumulates in the
kidney, which is reflected in a highly tidak normal excretion of sulfatide in urine
sediment. 8

 GENETICS
About 200 different ARSA mutations are known. The three more
frequent alleles among European patients are c.465+1G>A (traditional
denomination 459+1G>A) (severe phenotype), p.Pro428Leu (P426L)
(mild phenotype) and p. Ile181Ser (I179S) (mild phenotype). There is a
relatively good genotype-phenotype correlation [84]. Two very frequent
ARSA polymorphisms, one leading to the loss of an N-glycosylation site
and the second to the loss of a polyadenylation signal, result in reduction
of the amount of enzyme and constitute the molecular basis of ASA
pseudodeficiency.9
They often occur jointly, but can also be found independently. In
some countries, as many as 15% of the general population carry one allele
with such a pseudodeficiency (pd). MLD due to sap-B deficiency is

16
 panethnic, but seems more frequent in Saudi Arabia, Turkey and North
Africa. These patients have mutations (10 described to-date) in PSAP.9

3.1.3. CLINICAL MANIFESTASIONS

When juvenile patients struggle to reach expected developmental milestones after

previously being able to do so, leukodystrophies are typically considered.
Dysarthria and other CNS symptoms can appear before peripheral
neuropathy.10,11 At any age, a person should have metachromatic leukodystrophy
assessed if their gross and fine motor skills are deteriorating. The age at which a
disease first manifests itself might be used to categorize its clinical presentations. 12

 Late infantile onset: . is the most common. First symptoms appear

between the ages of 1 and 2 years( median onset 18 months): walking
delay, progressive difficulty in locomotion around 14–16 months( weaker
lower limbs and falls); 15% of children never walk independently.
Examination usually shows hypotonia, reduced or absent deep tendon
reflexes and extensor plantar responses. Walking and then standing soon
become impossible. The child develops spastic quadriplegia, speech
deterioration, berangsur- angsur psikologis regression and optic atrophy
leading to blindness, followed by a vegetative state and death.12,13

 Juvenile onset: between the ages of 30 months and adolescence, with a

variety of presentations. Early developmental milestones are attained, then
there is psychomotor regression, intellectual deterioration( ex., decreased
grades), behavioral issues, personality changes, ataxia, upper motor neuron
symptoms, and peripheral neuropathy. Similar symptoms, including +/-
seizures, are found in late juvenile-onset patients. Dementia, memory loss,

17
 loss of inhibition, impulsivity, impaired motor function, and optic atrophy
are all seen in neurocognitive testing.13,14

 Adult onset: Two distinct types of adult MLD have been identified[87]. In
the first group, patients have predominant motor disease, with pyramidal
and cerebellar signs, dystonia and peripheral neuropathy, or isolated
peripheral neuropathy. In the second group, behavioural and psychiatric
problems( often confused with schizophrenia) are the presenting
symptoms, followed by dementia and spastic paresis. 13

3.1.4. EVALUATION

Laboratory Studies:

Arylsulfatase Leukocytes or skin fibroblasts in culture may have diminished

enzyme activity.15 Values often fall between undetectable and less than 10% of the
average values. However, arylsulfatase A pseudodeficiency must be separated
from metachromatic leukodystrophy (present in approximately one percent of the
general population). those World Health Organization have arylsulfatase
Arylsulfatase A levels between 5% and 20% of values without any clinical or
radiographic illness are indicative of a kuasi deficient. The tests listed below can
be used to distinguish between them:

• Urine sulfatide levels

• Radiolabeled sulfatide fibroblast loading

• DNA mutation analysis or next- generation sequencing- biallelic ARSA

pathogenic variants

Imaging Studies

T2- weighted FLAIR symmetric and confluent hyperintensities are nonspecific

but characteristic of the illnesses and can be seen on brain MRI in the langsung

18
and parietal periventricular white matter. Given that the condition is
demyelinating, T1-weighted pictures are frequently hypointense. Metachromatic
leukodystrophy is not ruled out by a normal MRI.16

Hyperplastic gallbladder polyps, which increase the risk of gallbladder cancer,

may be seen on an abdominal ultrasound or CT scan.17

Additional Tests

The tests that are listed below can be carried out to help with the case's diagnosis.

• Nerve conduction and ENG studies

o An EMG pattern indicative of demyelinating polyneuropathy might influence

both sensory action potentials and compound muscular action potentials( CMAPs)
( SNAPs)

• Neurocognitive, neuropsychological testing, or both

Procedures

• Elevated cerebrospinal fluid protein content may aid in th following lumbr

puncture.

• Peripheral nerve biopsy: usually not performed, but may reveal metachromatic
lipid deposits

Newborn Screening

 It's still being worked on. Mass spectrometry is employed. It cannot be

separated from a false deficiency, though.18

3.1.5. TREATMENT

19
 Since there are presently no curative alternatives for this illness, the
emphasis is on symptom management to improve quality of life. Neurocognitive
and neuropsychiatric abnormalities, seizures, dystonias, spasticity, eating issues,
and constipation all require symptomatic supportive care.

Symptomatic Treatment

• Seizures: broad- spectrum antiepileptic drugs such levetiracetam, zonisamide,

lacosamide, and valproic acid can be used to treat seizures.

• Spasticity- baclofen, cyclobenzaprine, botox toxin A

• Dystonia- botox toxin A

• Fludrocortisone, midodrine, or anticholinergic pengobatan for

dysautonomia( drooling, orthostasis);

• Medicines for pain, such as NSAIDs, gabapentin, pregabalin, and SNRIs

• Nutritional and gastrointestinal problems: famotidine or pantoprazole, bowel

regimen( docusate, senna)

• Insomnia atau mood problems: SNRIs like mirtazapine, TCAs, SSRIs, etc.

• Physical, occupational, cognitive, and gait for arthritis atau myalgias, mobility
issues, and functional limitations in daily living 19

Genetic Counseling

MLD has an autosomal recessive inheritance pattern. Each affected persons

sibling has a 25% chance of developing the disease, a 50% chance of becoming an
asymptomatic carrier, and a 25% chance of being unaffected and not a carrier at
conception. If both ARSA pathogenic variants have been found in an affected

20
family member, carrier testing of at- risk family members and prenatal testing for
a pregnancy at elevated risk are also options.

Experimental and emerging therapies:

 A combination of gene therapy and hematopoietic stem cell

transplantation (HSCT)- now shows the most promise. The advantages
might be more noticeable in juvenile-onset diseases that are asymptomatic
or have mild symptoms. For those with symptomatic late-infantile form,
HSCT is not advised. According to studies, the 5-year survival rate for
patients with juvenile illness may be around 59%. But many patients reject
post-transplant care (based on measures such as imaging, gross motor
function, cognitive skills, nerve conduction velocities, and other metrics).
Consequently, bone marrow transplantation may stabilize neurocognitive
performance; nonetheless, there is still a progressive loss of motor ability.
The course of the disease may be slowed by bone marrow transplantation
in late juvenile and adult onset types.20,21
o Phase I/II clinical trial gene therapy (using retroviral vector
technology) plus autologous hematopoietic stem cell
transplantation: A study of asymptomatic juvenile diseases,
infantile diseases, and early-onset juvenile diseases revealed
delayed onset of MRI abnormalities and recovery of some
cognition and gross motor function.22,23

 Gene therapy, enzyme replacement, and small molecule therapy (e.g.,

substrate reduction and chaperone therapies)

Therefore, preliminary research suggests that gene therapy and gene therapy
paired with hematopoietic stem cell transplantation are viable pengobatan
alternatives. Metachromatic leukodystrophys cellular etiology is complicated,
though. With some success, disease- specific gene and enzyme substitution
therapies have been used for a number of additional LSDs. Emergent therapeutics
for various LSDs include small- molecule treatments. Phase III atau IV clinical

21
trials are required even though gene therapy and genome microRNA editing are at
advanced preclinical phases. 24

3. 1. 6. DIFFERENTIAL DIAGNOSIS

Metachromatic leukodystrophy must be differentiated from other LSDs with

similar presentation and with arylsulfatase A pseudodeficiency. Arylsulfatase A
pseudodeficiency can be differentiated using gene mutation analysis or evaluation
of radiolabeled sulfatide fibroblast uptake and accumulation. Other differentials
that must be kept in mind while diagnosing metachromatic leukodystrophy are:

• Krabbe diseases: LSD that is autosomal- recessive, caused by deficient activity

of the beta- galactosidase. Clinically it presents with irritability, hypertonia,
hyperesthesia, and psychomotor arrest. 25- 26

• X- linked adrenoleukodystrophy: Primarily affects boys, it is a leukodystrophy

that presents with adrenal insufficiency, neurocognitive( low Intelligence
Quotient(IQ)) and neurobehavioral issues( ADHD- like behavior), dysarthria,
dysgraphia, deficits in vision, hearing. They are found to have elevated very-
long- chain fatty acids( VLCFA), tidak normal white matter disease on MRI, and
a pathogenic variant of the ABCD1 gene on molecular genetic testing. 27- 28

• Canavan disease: Primarily affecting the Ashkenazi Jewish population, it is an

infantile autosomal- recessive leukodystrophy characterized by intellectual
disability, irritability, macrocephaly, dysphagia, early hypotonia, late spasticity,
ataxia, seizures, and optic atrophy. It is progressive and neurodegenerative in
nature. Typically they have elevated N- acetyl aspartate( NAA) in air kemih, tidak
normal diffuse white matter disease on MRI, and pathogenic variants in ASPA on
molecular genetic testing. 29- 30

• Peroxisomal biogenesis disorders( e. gram. Zellweger disease): Leukodystrophy

caused by a mutation in one out of 13 different PEX genes, PEX1 being the most

22
common, leading to dysfunctional peroxisomes. Clinical symptoms may include
intellectual delay, craniofacial dysmorphia, retinopathy( e. gram. glaucoma,
retinitis pigmentosa), visual blindness, sensorineural deafness, hypotonia,
hepatomegaly with coagulopathy, diffuse jaundice, dysphagia, chondrodysplasia
punctata, and seizures. MRI can show neocortical dysplasia, diffuse white matter
atrophy, and ventriculomegaly with cysts. Elevated transaminases and
hyperbilirubinemia are common. 31- 32

• Polyglucosan body disease: An autosomal recessive adult- onset disease

characterized by progressive neurogenic bladder, gait difficulties( e. gram.
spasticity and weakness) from mixed upper and lower motor neuron involvement,
sensory loss predominantly in the distal lower extremities, and some cognitive
difficulties( often executive dysfunction). MRI of the brain and spinal cord, and
sural nerve biopsy shows clusters of polyglucosan deposition. The glycogen
brancher enzyme( GBE) activity in skin fibroblasts is tidak normal, and molecular
genetic testing reveals a mutation in GBE1. 33- 34

• Fucosidosis: very rare, caused by FUCA1 mutation, characterized by coarse

facies, recurrent opportunistic infections, generalized dystonia, spasticity,
dysostosis multiplex, diffuse angiokeratoma, and organomegaly. 35- 36

• Childhood- onset schizophrenia: Childhood- onset schizophrenia is a severe

form of psychotic disorder that occurs at age 12 years or younger. It has some
neurologic features and has to be differentiated from metachromatic
leukodystrophy. Schizophrenia presents with delusion, hallucinations,
disorganized speech, grossly disorganized or catatonic behavior, and negative
symptoms. 37

3. 1. 7. PROGNOSIS

Metachromatic leukodystrophy is a progressive disease. This means that the

symptoms tend to get worse berlebihan time. People World Health Organization

23
have this disease lose all muscle and psikologis functions eventually. Lifespan
often depends on the age at which a individu is first diagnosed.

• Late infantile form: The diagnosis is worse than later- onset forms of the
diseases; progression to death typically occurs within five to six years.

• Juvenile form: Progression is slower in this form of the disease, and the patients
may survive until early adulthood.

• Adult form: The disease course in this form of the disease may be static or of
insidious progression.

CHAPTER IV
CASE ANALYSIS

The genetics of the lysosomal storage disorder known as metachromatic

leukodystrophy are well characterized, and when patient groups are examined, a
genotype-phenotype link is seen. When juvenile patients struggle to reach
expected developmental milestones after previously being able to do so,
leukodystrophies are typically considered. Dysarthria and other CNS symptoms
can appear before peripheral neuropathy. From the anamnesis, since the age of 8
years the child has complained that when he walks he suddenly falls, falls and
sometimes hits his head, the child has not complained of headaches, no pain in
both legs. The child also begins to behave strangely, sometimes laughing, crying
or getting angry for no reason, if someone is nearby the child tends to hit the
person often. Parents take their children to see a doctor at the Puskesmas, then
they are advised to go to a hospital in Pati. However, parents only take their

24
children for treatment to the village shaman. 4 months after the first complaint the
child started having seizures, seizures in all limbs, the duration of the seizure was
approximately 1 minute, the seizures stopped by themselves, the child realized
after the seizure. Seizures without fever. The mother did not take the child for
treatment, repeated seizures in 1 week 3 seizures with the same type and pattern.
The longer the seizures, the more frequent, almost every day the child has seizures
with seizures lasting up to 5-10 minutes. The child was then taken to the hospital
for treatment. Starch. A CT scan was performed, but it was said that there were no
abnormalities. It is recommended to be referred to the hospital. Kariadi, but
parents do not want. The child received anti-seizure drugs, piracetam, phenytoin
and valproic acid. Children routinely control to the hospital. Starch to get anti-
seizure drugs, but complaints of seizures do not improve.

In May 2019 the child was referred to the hospital. Telogorejo for EEG,
obtained the impression of visible epileptiform waves, with ictal EEG spikes,
slow spike waves. Children still have complaints of recurrent seizures almost
every day. Children are advised to go to the hospital. Kariadi but parents refused.
In December 2019 the child could not walk at all, the child only fell asleep, his
hands and feet were stiff, sometimes he could sit up. The child also has no contact
with the parents, the seizures are still recurring. The child was referred to the
hospital. Kariadi for an MRI examination, and just received an MRI schedule for
February 2020. February 2020 the control child went to the hospital's neurology
polyclinic. Kariadi with MRI results, diagnosed with epilepsy and suspected of
having an inborn error in metabolism, received anti-epileptic kepra and valproic
acid. Since there are presently no curative alternatives for this illness, the
emphasis is on symptom management to improve quality of life. Neurocognitive
and neuropsychiatric abnormalities, seizures, dystonias, spasticity, eating issues,
and constipation all require symptomatic supportive care.10

The child is then consulted to the nutrition and metabolic disease

polyclinic for diagnosis. Children are programmed to be hospitalized via TPPRI.
According to theory patient seizure and decrease development, Failure in school,
behavioural problems or disturbance of cognitive function may precede motor

25
abnormalities, especially in patients with a later onset (>6 years). Progressive
difficulties in walking, cerebellar ataxia constitute the most common presentation,
but various other symptoms can occur, such as hemiplegia, dystonia and
choreoathetosis. Seizures may also develop.8 A severity scoring based on a gross
motor function classification has been developed for late infantile and juvenile
forms. age onset age 11 years from the history diagnosis support to
Metachromatic leukodystrophy juvenile onset.9
From the physical examination, the child is apatis, vital signs show blood
pressure 90/60 mmHg, heart rate 88 bpm, respiratory rate 18 breaths/minute,
temperature 36,40C, oxygen saturation 99% room air, regular and adequate pulse.
Body weight 19.6 kg, body length 133 cm, WAZ NA, HAZ -2.33 SD, BMI -4.66
SD. pupils were equal, round and decrease reactive to lights, with diameter 4
mm/4mm, no conjunctiva anemic, no palpebra edema. Ears were clear, no
discharge. There was no nasal flaring, no nasal discharge. Mouth mucous
membrane was moist, no cyanosis. Neck examination revealed no
lymphadenopathy. Chest expansion was symmetrical and no retraction was
visible. Heart sounds were normal, with no murmur or gallop. On lungs
auscultation, basic sound vesicular was normal, no crackles, no rhales, no
wheezes. Abdomen was soft, flat, liver and spleen were not palpable, skin turgor
returned quickly. Extremities were warm, no cyanosis, no edema, capillary refill
less than 2 seconds, muscle wasting (+), increase on physiological reflexes in
fourth extremities, no pathological reflexes, spastik (+).In most patients, motor
nerve conduction velocities of peripheral nerves are decreased and sensory nerve
action potentials have a diminished amplitude with a prolonged peak latency.
Decreased nerve conduction is not always present in adult MLD.8
The patient has been subjected to various supporting examinations to establish the
diagnosis. Routine complete blood count electrolytes and BGA were within
normal limits. MRI examination of the patient's image Hiperintens lesion T2WI
dan T2FLAIR in frontal area, temporal, and right and left parietal white matter
suspect inborn error metabolism, still possible leukodystrophy dd/ metachromatic
leukodystrophy, alexander disease. MRI shows similar fairly characteristic
symmetrical changes of the central white matter in all forms. A sheetlike zona of

26
tidak normal T2 signal hyperintensity initially envelops the langsung and parietal
periventricular and central white matter regions, faint in mild disease and denser
in moderate to severe disease. As severe disease develops, the sheet of white
matter signal intensity abnormality also involves the inner half of the subcortical
white matter, and a tigroid pattern emerge 8, 12

27
 CHAPTER V
SUMMARY

Metachromatic leukodystrophy is a lysosomal storage disease, which is well

understood at the genetic tingkat and for which a genotype–phenotype correlation
exists when groups of patients are compared. The phenotypic variation amongst
patients with the same genotype is, however, substantial, so it remains impossible
to predict the perseorangan disease course based on genetic informasi alone. The
animal bentuk currently available for the disease does not develop the widespread
demyelination seen in patients, although the mice store sul- phatide in the same
tissues as humans. Therefore, the use of ASA- deficient mice in pathogenic
studies and studies examining the prevention and reversibility of myelin
degeneration is very limited. Juvenile dermatomyositis is a very rare disease. This
case discusses a 11- year- old girl with complaints seizures, seizures in all
extremity, the duration of the seizure was approximately 1 minute, the seizures
stopped by themselves, the child was conscious after the seizure. Seizures without
fever, In December 2019 the child could not walk at all, the child only fell asleep,
his hands and feet were stiff, sometimes he could sit up. The child also has no
contact with the parents, the seizures are still recurring. The child was referred to
the hospital. Kariadi for an MRI examination results, diagnosed with epilepsy and
suspected of having an inborn error in metabolism, The child is then consulted to
the nutrition and metabolic disease for diagnosis, a history, complete physical
examination and supporting examinations were suspected Metachromatic
leukodystrophy.

28
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