Late juvenile metachromatic leukodystrophy (MLD) in three patients with a similar clinical course and identical mutation on one allele

Abstract

Metachromatic leukodystrophy (MLD) is an autosomal, recessively inherited, lysosomal storage disease caused by arylsulfatase A (ASA) activity deficit. Arylsulfatase A initiates the degradation of sulfatide (cerebroside sulfate), which is an essential component of myelin. The main clinical symptoms are caused by progressive demyelination. At least 37 MLD‐related ASA mutations are known to date. I179S (E3P799) is a disease‐related mutation, described for the first time by Fluharty in 1991. This aberration appears to substantially reduce, but not completely eliminate ASA activity, and was detected in individuals with late‐onset (juvenile or adult) forms of MLD. This paper deals with the peculiar clinical course in three unrelated juveniles with late‐onset MLD carrying the I179S mutation on one allele. In the three described patients with the I179S mutation, psychiatric disturbances and intellectual impairment dominated the clinical picture, while the neurological lesions progressed more slowly. Although the symptoms appeared rather early, making it possible to classify this as the juvenile type of MLD, the clinical picture was more that of the adult type. Although the mutations on the second allele in our patients are unknown, one can speculate, that the mutation I179S plays an important role in the characteristic clinical course (psychiatric impairment, slower neurological deterioration, but relatively early onset). It seems that I179S mutation on one allele with another mutation on the other allele reduces ASA activity, but the enzyme can still cope with a part of the substrate influx, leading to late‐juvenile‐onset MLD with such strikingly similar phenotypes remaining a little bit of the adult (psychiatric) type. This could be one more argument in favour of phenotype‐genotype correlation in patients with MLD.

Sulfatide Storage in Neurons Causes Hyperexcitability and Axonal Degeneration in a Mouse Model of Metachromatic Leukodystrophy

“…Late-onset (adult) MLD is characterized by low residual ASA activity (von Figura et al, 2001). Characteristic symptoms in adult MLD are schizophrenialike behavioral abnormalities [in patients with the I179S mutation (Tylki-Szymanska et al, 1996)] or clumsiness of movement and spastic paresis of arms and legs [in patients with the P426L mutation (Berger et al, 1997)]. In contrast, nerve conduction velocity is sometimes normal, and signs of peripheral neuropathy and demyelination are often absent (Kolodny and Fluharty, 1995).…”

Late-onset metachromatic leukodystrophy

“…Among these, two different clinical presentations have been observed: patients with progressive motor or sensory deficits and, on the other hand, cases with mental disturbance. [3][4][5][6][7][8][9][10][11][12] It has been suggested that these differences may originate from different specific mutations. 1,7,12 To explore a possible genotype-phenotype correlation in late-onset MLD on the basis of specific mutations, we studied the molecular and clinical data of 22 patients homozygous for mutation P426L and of 20 patients heterozygous for mutation I179S.…”

Adult metachromatic leukodystrophy: a new mutation in the schizophrenia-like phenotype with early neurological signs

“…The number of mutations found so far in adult MLD patients is quite limited. Beside a common missense mutation, P426L, predominantly found in patients with motor disturbances, another missense mutation, I179S, was found in adult MLD patients (Tylki-Szymanska et al, 1996;Halsall et al, 1999;Baumann et al, 2002).…”

“…Whereas Gieselmann et al (1994) showed that most adult motor forms of MLD present with a specific homozygous missense mutation, P426L, Baumann et al (2002) and others (Tylki-Szymanska et al, 1996;Halsall et al, 1999) reported on patients with the psycho-cognitive form, who were heterozygous for a specific mutation, I179S, together with an allele found in infantile cases. Recently, a homozygous patient with a novel mutation, F219V, a woman with progressive psycho-cognitive impairment without clinical or electrophysiological signs of peripheral nerve involvement, has been described (Maracao et al, 2005).…”