Massive CAG repeat expansion and somatic instability in maternally transmitted infantile spinocerebellar ataxia type 7.

IMPORTANCE: We report the first case to date of maternally transmitted infantile spinocerebellar ataxia type 7 (SCA7), in which a tract of (CAG)45 expands to lengths as large as (CAG)92-250. OBSERVATIONS: A 38-year-old woman with classic SCA7 (and a son, who died at age 3 years) had pronounced cerebellar atrophy and a renal biopsy specimen that showed focal segmental glomerulosclerosis with abnormal podocytes containing cytoplasmic inclusions. Polymerase chain reaction amplification across the SCA7 repeat tract assessed expansion levels in tissues of the affected son. High levels of somatic CAG instability were observed in blood, kidney, and skeletal muscle. This transmitted expansion is considerably larger than previously reported maternal transmission expansions of 5 to 10 gained repeats. CONCLUSIONS AND RELEVANCE: We document the first intertissue CAG instability reported to date in patients with SCA7, similar to SCA7 mouse models. Infantile SCA7, which is often paternally transmitted, can rarely arise by maternal transmission, which has implications for diagnosis and counseling among families of patients with SCA7.

Angelman syndrome due to a termination codon mutation of the UBE3A gene.

Angelman syndrome is a neurodevelopmental disorder characterized by global developmental delay, mental retardation, seizures, microcephaly, and severe speech delay. It may be caused by deletion of chromosome region 15q11.2 of the maternally inherited chromosome, mutations in the UBE3A gene, uniparental disomy, or imprinting defects. Most patients with this diagnosis have a severe phenotype, and a few have a mild form of the disease. We report a patient with a novel mutation in the UBE3A gene that consists of a deletion of the termination codon (c.2556-*+6del GTAAAACAAA) and results in an elongated protein E3 ubiquitin-protein ligase. Our patient has a mild phenotype compared with other patients in general and specifically to patients with UBE3A mutations. He has mild developmental delay, moderate speech delay, and no seizures. Recognition of this genotype-phenotype correlation will allow better genetic counseling to other patients with similar stop codon mutations.

Transient fulminant liver failure as an initial presentation in citrullinemia type I.

Citrullinemia type I (CTLN1) is a urea cycle disorder which typically presents in the neonatal period or infancy with hyperammonemia and concurrent neurologic deterioration. We report a 15-month-old female with CTLN1 who presented with encephalopathy and seizures with hyperammonemia requiring emergency treatment. Although there was a rapid resolution of her hyperammonemia, she developed fulminant liver failure. The severe increase of transaminases (aspartate aminotransferase and alanine aminotransferase levels peaking at 19,794 UI/L and 19,938 UI/L, respectively) and concurrent disturbances in her hepatic synthetic functions led to the consideration of a liver transplantation. However, there was a normalization of her liver function tests over the course of weeks with supportive therapy alone. Molecular analysis of the ASS1 gene confirmed the diagnosis of CTLN1 by revealing the known mutation c.1087C>T (p.R363W) on the paternal allele and an intronic nucleotide exchange leading to an insertion of 69 bp on the transcript resulting in a frameshift and premature stop of translation on the maternal allele. We also briefly report another case of CTLN1 where liver failure was a prominent feature of the presentation. Fulminant liver failure has been described with a variety of other urea cycle disorders, but has been described in infantile onset presentation of CTLN1 in only two other cases recently. Our observation suggests that in some cases of CTLN1 with acute liver failure, emergency intervention such as transplantation is not warranted despite evidence of severe hepatotoxicity.