Striatonigral Degeneration, Infantile

A number sign (#) is used with this entry because of evidence that autosomal recessive infantile striatonigral degeneration (SNDI) is caused by homozygous mutation in the NUP62 gene (605815) on chromosome 19q13.

Description

Bilateral striatal necrosis (BSN) encompasses a heterogeneous group of neurologic disorders with different causation. Familial infantile striatal degeneration is rare and can be inherited as an autosomal recessive or mitochondrial (see 500003) disorder. The familial form has an insidious onset and a slowly progressive course; the sporadic form is associated with acute systemic illness. Many features of BSN overlap with Leigh syndrome (256000) and certain metabolic disorders, including glutaric acidemia I (231670) and methylmalonic aciduria (251000). See also Aicardi-Goutieres syndrome (225750) (Mito et al., 1986; De Meirleir et al., 1995).

Genetic Heterogeneity of Stiatonigral Degeneration

Childhood-onset striatonigral degeneration (617054) is caused by mutation in the VAC14 gene (604632) on chromosome 16q22.

See also adult-onset autosomal dominant striatal degeneration (ADSD; 609161), caused by mutation in the PDE8B gene (603390) on chromosome 5q13.

Clinical Features

This rare disorder was probably first described by Paterson and Carmichael (1924) who described patients with choreoathetosis, abnormal eye movements, seizures, and mental retardation. In some patients, the symptoms appeared after a febrile illness associated with nausea and vomiting. The main neurologic finding was symmetrical degeneration of the caudate nucleus and putamen and sometimes of the globus pallidus. Paterson and Carmichael (1924) described in detail 2 sibs; 10 of 12 sibs had died under 2 years of age. Miyoshi et al. (1969) described 3 sibs in 1 family and 2 sibs in another. Roessmann and Schwartz (1973) reported 2 sibs. Mito et al. (1986) divided the 27 reported cases into 3 groups with characteristic clinical and pathologic features: an early acute-onset form (4 cases), an early gradual-onset form (16 cases), and a late-onset form (7 cases).

Holtzman and Hedley-Whyte (1992) reviewed the case of a boy who died at 56 months of age of a progressive neurodegenerative disorder characterized by gradual loss of motor and verbal skills with generalized seizures, myoclonus, and final deterioration to a nonverbal, quadriparetic state. A sister had pursued a similar course. Both sibs showed cerebellar ataxia and marked cerebellar atrophy on MRI scans.

Straussberg et al. (2002) described an Israeli Bedouin kindred with familial IBSN with an apparently autosomal recessive mode of inheritance. They evaluated the clinical and radiologic evolution of the disease in 11 patients and the cerebral pathologic findings in 1. Three of the children were treated with oral biotin (100 mg/day) on the basis of its successful use in another form of basal ganglia disease (607483). The untreated children had a similar clinical picture, including developmental arrest beginning at the age of 7 to 15 months, choreoathetosis, and dysphagia. Pendular nystagmus appeared at a late stage. MRI, performed at various stages of the disease, showed severe basal ganglia atrophy. Postmortem study in one patient showed severe atrophy of the lenticular nuclei with gliosis and loss of neurons. Biotin, administered to the proband over a period of 15 months, may have slowed progression. In 2 other children, treatment was administered earlier and appeared to arrest or improve the disorder. It was notable that lactate and pyruvate levels were normal in these patients.

Basel-Vanagaite et al. (2004) reported 10 patients with infantile bilateral striatal necrosis from 6 consanguineous Israeli Bedouin families, 1 of which had been reported by Straussberg et al. (2002). The clinical features were similar in all families.

Inheritance

Straussberg et al. (2002) pointed out that IBSN encompasses several syndromes of bilateral symmetric, spongy degeneration of the caudate nucleus, putamen, and globus pallidus. The familial form of IBSN is rare, and inheritance is either autosomal recessive or maternal (i.e., mitochondrial).

Mapping

By linkage analysis in 6 Israeli Bedouin families with infantile bilateral striatal necrosis, Basel-Vanagaite et al. (2004) identified a 1.2-Mb candidate disease region between D19S596 and D19S867 on chromosome 19q13.32-q13.41 (maximum lod of 6.27 at D19S412). Haplotype analysis suggested a founder effect. The authors noted that an adult-onset basal ganglia disease (606159) maps to the same region and is caused by mutation in the gene encoding ferritin light chain (FTL; 134790); however, no mutations in the FTL gene were identified in the Bedouin families.

Molecular Genetics

In 12 affected individuals from 8 Israel Bedouin families with IBSN, including 6 families described by Straussberg et al. (2002) and Basel-Vanagaite et al. (2004), Basel-Vanagaite et al. (2006) identified a homozygous mutation in the NUP62 gene (Q391P; 605815.0001). Haplotype analysis indicated a founder effect. Five prenatal diagnoses were performed in 3 at-risk families, and 2 fetuses were found to have the disorder. Sequencing of 12 additional genes within the candidate region showed no pathogenic changes.