1. Metachromatic Leukodystrophy
GR. Zamani MD.
Child Neurologist
Tehran University of Medical Sciences(Tums),Nov 2014

2. Leukodystrophies are genetic disease with degradation of myelin sheath in CNS & sometimes also in PNS
The basic defect is in synthesis & maintenance of myelin membrane
Most incurable, progressive course leading to premature death
Diagnosis is important for experimental therapies, reproductive counseling, screening of unaffected cases & early treatment in few cases
Introduction

3. How to approach Making diagnosis of Leukodystrophies require:
Knowledge of clinical features & Neuroimaging
Familiariy with age of onset, brain MRI pattern, Electrophysiologic findings, specific Lab tests &Genetic t for confirmation
How to approach

4. An 18 months old boy with complaint of spasticity and regression
Product of consanguineous marriage
Other siblings were normal
No family hx of same problem
Case History

5. Case Cn’d Normal cognition Weakness Brisk DTR
Bilateral babiniski signs.
Case Cn’d

6. Investigation Routine Metabolic screening : WNL
CSF : Normal Cell & Suger, increased protein level(68mg/dl).
EMG/NCV : No involvement
Investigation

7. Imaging

8. Imaging

9. Enzyme study was positive for deficient Arylsulfatase A.
Diagnosis

10. It is caused by deficient activity of Arylsulfatase A .
In almost all cases, mutations in the arylsulfatase A gene (ARSA gene).
In a few patients, MLD is caused by a deficiency of sphingolipid activator protein SAP-B (Saposin B), which stimulates the degradation of sulfatides by ARSA. This variant form of MLD is caused by mutations in the prosaposin gene (PSAP gene).
Pathophysiology

11. ARSA is responsible for the desulfation of cerebroside sulfate, a major glycolipid of myelin.
As a result, decreased ARSA activity leads to accumulation of cerebroside sulfate in CNS, peripheral nerves, kidneys, and other visceral organs.
Pathophysiology Cn’d

12. At least 60 mutations in the ARSA gene have been described in MLD.
Two alleles, A and I, together account for approximately 50 percent of cases and contribute to the different clinical expressions of the disease
GENETICS

13. Homozygosity for the I allele is associated with very low or undetectable residual ARSA activity and late infantile onset; compound heterozygotes (I with other allele unknown) also lead to late infantile onset.
Homozygosity for the A allele is associated with low but detectable residual ARSA activity and the juvenile or adult onset forms; compound heterozygotes(A+other) have later onset of disease
The presence of both alleles(A+I) is associated with juvenile onset.
Genetics(2)

14. CLINICAL MANIFESTATIONS
 Three major types Late infantile,Juvenile,adult form of metachromatic leukodystrophy (MLD) are primarily distinguished by the age at disease onset.
Peripheral neuropathy occurs in all forms and may be a presenting feature, particularly in the late infantile form
CLINICAL MANIFESTATIONS

15. The late infantile form typically appears at six months to two years of age.
Early signs include motor regression, gait difficulties, ataxia, hypotonia, Babinski sign, and optic atrophy.
Reduced DTR, reflects peripheral neuropathy.
This disorder progresses rapidly to death within five to six years.
Late infantile onset 

16. Juvenile and adult onset
The juvenile onset form is heterogeneous in presentation. Some children present between four and eight years of age (early juvenile) motor involvement, intelectual impaiment are main symptoms.Seizures may occur, and progression to death occurs within six years of onset.
Another group of children present between 6 and 16 years of age (late juvenile) with behavioral changes and intellectual impairment and, in many cases, seizures. Progression is slower, and these children may survive until early adulthood.
Juvenile and adult onset

17. Phenotypic presentation in Late onset
Late-onset MLD patients(late juvenile & adult )
who are homozygous for ARSA mutation P426L generally present with progressive gait disturbance (spastic paraparesis or cerebellar ataxia), while mental involvement becomes evident later.
In contrast, compound heterozygotes for ARSA mutation I179S present with schizophrenia-like behavioral abnormalities, social dysfunction, and mental decline, but motor deficits are scarce.
Phenotypic presentation in Late onset

18. Diagnostic Approch Clinical picture Reduced NCV Elevated CSF protein
MRI reveals symmetric white matter lesions in the early form of the disease and cortical atrophy in the later forms.
Diagnostic Approch

19. Deficient ARSA activity in leukocytes or cultured skin fibroblasts( ranges from undetectable to less than 10 percent of normal values).
Diagnosis based only on the activity of ARSA is complicated by the existence of ARSA pseudodeficiency
As a result, screening for pseudodeficiency alleles is important when low but not absent levels are detected in prenatal testing or screening of asymptomatic relatives
DIAGNOSIS 

20. All in All Definite diagnosis will put an end to long & distressing efforts to diagnostic search ,
Let the parents focus on palliative & available options,
Facilitates more realistic view of the family & further genetic counseling.
Diagnostic necessity

21. TREATMENT curative treatment is currently not available for (MLD).
BMT has in some patients slowed disease progression
Preliminary evidence suggests that gene therapy, or hematopoietic stem cell transplantation combined with gene therapy, is a promising option