Adult Metachromatic Leukodystrophy (problems of differential diagnosis)
MICHAEL M., SAVVIDOU C., HONDROMATIDOU S., MICHELAKAKI H., FITSIORIS X., GEORGIADIS G.

Metachromatic leucodystrophy (ΜLD) is a rare neurological disorder first described by Alzheimer 92 years ago. It is an autosomal recessive lysosomal disorder characterized by demyelinization of the white matter in the central nervous system and peripheral nerves. The gene is located on chromosome 22q13. At least 87 ASA (arylsulfatase A) mutations that are pertinent to MLD have now been identified. Some ASA mutations result in residual enzyme activity, and are associated with milder clinical phenotypes. The disease is caused by a deficiency of arylsulfatase A (ASA) enzyme, which hydrolyzes various sulfatides, including galactosyl sulfatide and lactosyl sulfatide, major sulfate-containing lipids of the nervous system. The diagnosis of ΜLD is based on decreased ASA activity in leukocytes or fibroblasts and accumulation of sulfatides which can be found in the brain, peripheral nerves and non neural organs (kidney, liver gallblader etc). The clinical forms of the disease have been distinguished by age of onset ( late infantile, juvenile, adult). The age of onset appears to be related to the degree of enzyme deficiency. The greater the degree of preserved biological activity of arylsulfatase A, the later the onset of symptoms. Late infantile form is usually manifest by ages of 1.5-2 years. Children develop a gait abnormality with hyptotic diplegia, ataxia, progressive weakness and cognitive abnormalities. There is rapid progression over the next 1-2 years with progressive hypotonia, weakness and intellectual deterioration. Late stages of late infantile form are characterized by loss of speech, spasticity, decerebrate posturing and death usually by 5 years of age. Juvenile form of MLD manifests between 4 and 12 years of age. A previously well child develops a spastic gait, ataxia and intellectual deterioration. Patients develop increasing spasticity and dementia with episodes of decerebrate posturing and generalized tonic-clonic seizures. The disease progresses more slowly than late infantile MLD. Adult form of MLD may begin at any age beyond puberty, but usually presents between the third and fourth decades of life. A change in personality or poor job or school performance may herald the onset of the disease. Defective visual-spatial discrimination, poor memory, disorganized thinking and decreased mental alertness are observed. In addition to intellectual and emotional changes, general slowness and clumsiness are also presenting features of the illness. Mean survival is usually 5 to 10 years, which is longer than the survival in late-infantile MLD (3 to 4 years) and juvenille MLD (7 to 9 years). Compared with late infantile MLD in which motor symptoms predominate in the early stage, it seems that a combination of mental and behavioral symptoms and ataxia predominated in the adult form of MLD. Adult form generally presents as dementia or psychiatrics disturbances. Psychiatric symptoms, including complex auditory hallucinations and bizarre delusions, are a prominent feature of MLD presenting when the patient is between 12 and 30 years. Psychosis in adolescent and early-onset MLD is much more frequent than in selected surveys of Huntington disease or temporal lobe epilepsy. In addition to auditory hallucinations, other behavioral manifestations bear a striking resemblance to aspects of schizophrenia. These include, thought fragmentation, catatonic posturing, bizarre gesturing, poor concentration and poor insight. In the absence of hard neurological signs it is not surprising that many of these patients may be considered to suffer from schizophrenia or other primary psychotic disorders. As in late-infantile and juvenile MLD , epilepsy tends to be a late feature and seldom the first.

Polyneuropathy is seldom the first clinical symptom. There have been described cases of Adult onset of metachromatic leukodystrophy presenting as isolated peripheral neuropathy. The finding of normal peripheral nerve conduction velocities does not exclude the possibility of adult MLD. On the other hand, a combination of evoked potentials and peripheral nerve conduction studies may be a useful step in detecting patients with adult MLD. Diagnosis is confirmed by demonstrating a deficiency of ASA activity in leukocytes or cultured skin fibroblasts, increased urinary sulfatides levels and by sural nerve biopsy. Determination of ASA deficiency alone is insufficient for a diagnosis of MLD because a pseudodeficiency (PD) state has been observed. In the PD state, low ASA activity is not accompanied by accumulation of sulfatides in the organs.

MRI studies reveal a distinct inhomogeneous pattern of diffusely abnormal white-matter signal in the centrum semiovale. Linear and punctuate areas of normal white-matter signal interspersed with demyclinated areas produce a tigroid or leopard-skin appearance. This tigroid pattern has previously been thought to be characteristic of Pelizaeus-Merzbacher disease.

We report a case of a 48 year old female patient, who 6 years ago, presented a deteriorating decline of intellectual functions, psychotic symptoms and gait disturbance.

Brain MRI, pathological neurophysiologic findings and the finding of arylsulfatase A iin the blood led us to the diagnosis of Adult Metachromatic Leukodystrophy.

Diagnosis of Metachromatic Leukodystrophy should be considered in cases of early dementia, with or without psychosis or other neurologic deficits, in which evoked potentials are delayed and peripheral nerve conduction is slowed.

Key words: Aggression, mental disorder, community, social support.