Leukodystrophy, Hypomyelinating, 3

A number sign (#) is used with this entry because of evidence that autosomal recessive hypomyelinating leukodystrophy-3 (HLD3) is caused by homozygous mutation in the AIMP1 gene (603605) on chromosome 4q24.

Description

Autosomal recessive hypomyelinating leukodystrophy-3 (HLD3) is a severe neurologic disorder characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system (summary by Feinstein et al., 2010).

The disorder is phenotypically similar to X-linked Pelizaeus-Merzbacher disease (PMD; 312080), which is caused by mutation in the PLP1 gene (300401). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.

Clinical Features

Early Descriptions

Nisenbaum et al. (1965) described a family in which 6 of 7 sibs (3 males and 3 females) died in the first months of life from an infantile disease resembling Pelizaeus-Merzbacher disease. The parents, Yemenite Jews, were apparently unrelated. All 6 affected children were born prematurely with low birth weights. The main clinical feature was vomiting beginning at 1 to 3 weeks after birth and progressing to continuous projectile vomiting. Sarnat and Adelman (1973) described a single case.

Yokoi et al. (1985) reported 2 affected sisters and reviewed reports of other cases. Novotny (1988) reported a case with associated arthrogryposis multiplex congenita and death at age 19 days.

Cassidy et al. (1987) referred to the classic X-linked form of Pelizaeus-Merzbacher disease as type I and reported a female with what they referred to as the connatal or Seitelberger type (type II). They found reports of 16 patients from 11 families, including the description of 3 affected brothers (Seitelberger, 1954).

Begleiter and Harris (1989) reported a brother and sister with severe connatal PMD consistent with autosomal recessive inheritance. Clinical features included severe developmental delay, tonic-clonic seizures, ankle clonus, rigidity, and spastic quadriparesis. Optic discs were atrophic. Postmortem examination of the boy, who died at about age 5 years, showed poor myelination of the white matter and massive gliosis throughout the brain. The cerebellum showed severe neuronal loss and scarce myelin. Mild polymicrogyria was also observed.

Wolf et al. (2004) reported 2 unrelated girls with infantile onset of nystagmus, hypotonia, microcephaly, and seizures. One child later developed spasticity and the other myoclonus and dystonia. Both had essentially absent psychomotor development. Brain MRI showed almost complete absence of myelination and magnetic resonance spectroscopy of CSF detected highly elevated concentrations of N-acetylaspartylglutamate (NAAG). Genetic analysis excluded mutations in the PLP1 gene and the gene coding for glutamate carboxypeptidase II (FOLH1; 600934), which catabolizes NAAG.

Patients With Proven Mutations in the AIMP1 Gene

Feinstein et al. (2010) reported 7 individuals from an extended consanguineous Israeli Bedouin kindred with infantile onset of a severe rapid hypomyelinating neurodegenerative disorder similar to Pelizaeus-Merzbacher disease. All affected individuals had severe failure to thrive, microcephaly, and severe global developmental delay with mental retardation and lack of speech. Fast horizontal or rotary nystagmus was often the presenting sign at age 2 to 3 months. Other neurologic features included axial hypotonia and progressive spastic paraparesis with wasting of lower limbs and positive pyramidal signs. This resulted in progressive joint contractures and kyphoscoliosis becoming apparent at about 2 to 3 years of age. All had coarse faces, most had slow pupillary reflexes, 2 had seizures, and 2 had pale fundi. Extensive laboratory testing ruled out metabolic diseases. Brain MRI and MRS showed global cerebral atrophy, atrophy of the corpus callosum, and arrest of myelination/hypomyelination associated with decreased N-acetylaspartate levels. At the time of the report, 5 of the patients were still alive, at ages ranging from 16 months to 26 years.

In a comment on the report of Feinstein et al. (2010), Biancheri et al. (2011) stated that the clinical and neuroradiologic features of those patients seemed consistent with a cortical disease rather than a primary white matter disorder. Severe failure to thrive with a concordant reduced head circumference, a rapid neurologic deterioration progressing over the first months of life, and abnormal epileptiform EEG pattern suggested a cortical disease more than PMLD. Biancheri et al. (2011) further argued that in patients with true hypomyelination, brain atrophy is mild or absent, and this was not the case in the family presented by Feinstein et al. (2010). Boespflug-Tanguy et al. (2011) also commented on the article by Feinstein et al. (2010), suggesting that the patients described did not present the core clinical and neuroradiologic symptoms that define a hypomyelinating leukodystrophy since the patients had rapid neurologic deterioration, early microcephaly, dysmorphia, spastic paraparesis, limb deformities, and kyphoscoliosis. Boespflug-Tanguy et al. (2011) argued that these patients presented a complex phenotype and appeared to suffer from a primitive severe axonal disease rather than a hypomyelinating leukodystrophy. Feinstein et al. (2011) commented on the letters by Biancheri et al. (2011) and Boespflug-Tanguy et al. (2011), stating that their patients presented precisely as described in the severe (connatal) form of Pelizaeus-Merzbacher disease, and that their MRI results were well within the scope of a PMD-like phenotype.

Armstrong et al. (2014) reported a Filipino girl with a severe neurodegenerative disorder resulting in death at age 15 months. She presented with microcephaly at birth and developed intractable seizures at age 3 weeks. EEG showed hypsarrhythmia and focal seizures arising from the occipital region. She also had no visual reaction to light. Brain imaging showed myelin deficiency and progressive cerebral atrophy, and MR spectroscopy showed decreased N-acetylaspartic acid (NAA). The patient had arrested psychomotor development and was hypotonic, areflexic, and immobile, with markedly decreased muscle mass at age 13 months. Armstrong et al. (2014) concluded that the phenotype was consistent with a primary neuronal degenerative disorder with secondary hypomyelination.

Mapping

By genomewide homozygosity mapping of a large consanguineous Israeli Bedouin kindred with autosomal recessive hypomyelinating leukodystrophy, Feinstein et al. (2010) found linkage to a region on chromosome 4q23-q25 (maximum lod score of 4.25).

Molecular Genetics

In affected members of a large consanguineous Israeli Bedouin kindred with infantile onset of hypomyelinating leukodystrophy-3, Feinstein et al. (2010) identified a homozygous mutation in the AIMP1 gene (603605.0001).

In a Filipino girl with a severe neurodegenerative disorder resulting in early death, Armstrong et al. (2014) identified a homozygous truncating mutation in the AIMP1 gene (603605.0002). The mutation was found by whole-exome sequencing and segregated with the disorder.