Tuesday, January 31, 2017

Spinocerebellar ataxia type 13

Pulst SM. Spinocerebellar Ataxia Type 13. 2006 Nov 9 [updated 2012 Mar 1]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.

In the families described to date, the phenotype of spinocerebellar ataxia type 13 (SCA13) has ranged from slowly progressive childhood-onset cerebellar gait ataxia associated with cerebellar dysarthria and often accompanied by mild intellectual disability and occasional seizures to adult-onset progressive ataxia. Life span is not shortened and many persons live beyond age 70 years, but assistance with gait may be required as the disease progresses.
Diagnosis is based on clinical findings and molecular genetic testing of KCNC3 (also known as Kv3.3), the only gene known to be associated with SCA13.
Treatment of manifestations: Antiepileptic drugs for seizures; canes, walkers and other adaptive devices to help prevent falls; speech therapy and communication devices; feeding assessment if dysphagia is present. Prevention of secondary complications: Weight control. Surveillance: Evaluation by a neurologist at least annually, and more often in the event of acute exacerbation. Agents/circumstances to avoid: Alcohol and sedating drugs because they can exacerbate ataxia.
SCA13 is inherited in an autosomal dominant manner. Too little data are available to estimate the proportion of cases resulting from a new pathogenic variant. Each child of an individual with SCA13 has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for SCA13 is possible if the pathogenic variant in the family is known.

Gallego-Iradi C, Bickford JS, Khare S, Hall A, Nick JA, Salmasinia D, Wawrowsky K, Bannykh S, Huynh DP, Rincon-Limas DE, Pulst SM, Nick HS, Fernandez-Funez P, Waters MF. KCNC3(R420H), a K(+) channel mutation causative in spinocerebellar ataxia 13 displays aberrant intracellular trafficking. Neurobiol Dis. 2014 Nov;71:270-9.

Spinocerebellar ataxia 13 (SCA13) is an autosomal dominant disease resulting from mutations in KCNC3 (Kv3.3), a voltage-gated potassium channel. The KCNC3(R420H) mutation was first identified as causative for SCA13 in a four-generation Filipino kindred with over 20 affected individuals. Electrophysiological analyses in oocytes previously showed that this mutation did not lead to a functional channel and displayed a dominant negative phenotype. In an effort to identify the molecular basis of this allelic form of SCA13, we first determined that human KCNC3(WT) and KCNC3(R420H) display disparate post-translational modifications, and the mutant protein has reduced complex glycan adducts. Immunohistochemical analyses demonstrated that KCNC3(R420H) was not properly trafficking to the plasma membrane and surface biotinylation demonstrated that KCNC3(R420H) exhibited only 24% as much surface expression as KCNC3(WT). KCNC3(R420H) trafficked through the ER but was retained in the Golgi. KCNC3(R420H) expression results in altered Golgi and cellular morphology. Electron microscopy of KCNC3(R420H) localization further supports retention in the Golgi. These results are specific to the KCNC3(R420H) allele and provide new insight into the molecular basis of disease manifestation in SCA13.

Waters MF, Pulst SM. Sca13. Cerebellum. 2008;7(2):165-9.

Spinocerebellar ataxia 13 (SCA13), initially described in a four-generation French family, has now also been characterized in a large Filipino pedigree. Ongoing investigations continue to identify additional SCA13 families and individuals. Recently, studies have shown that mutations in the voltage-gated potassium channel KCNC3 are causative for SCA13. Sequence analysis of KCNC3 revealed mutations 1554G-->A (R420H) in the Filipino and 1639C-->A (F448L) in the French pedigrees. Both mutations alter KCNC3 function in a Xenopus laevis oocyte expression system. KCNC3(R420H), located in the voltage sensor of the channel, has no detectable channel activity when expressed alone, and strong dominant negative effects when coexpressed with wild-type KCNC3. KCNC3(F448L) shifts the activation curve in the negative direction and causes an approximately sevenfold slowing of channel closure. These mutations are expected to change the output characteristics of fast-spiking cerebellar neurons, where KCNC channels confer capacity for high-frequency repetitive firing.

Herman-Bert A, Stevanin G, Netter JC, Rascol O, Brassat D, Calvas P, Camuzat
A, Yuan Q, Schalling M, Dürr A, Brice A. Mapping of spinocerebellar ataxia 13 to
chromosome 19q13.3-q13.4 in a family with autosomal dominant cerebellar ataxia
and mental retardation. Am J Hum Genet. 2000 Jul;67(1):229-35.

We examined a large French family with autosomal dominant cerebellar ataxia (ADCA) that was excluded from all previously identified spinocerebellar ataxia genes and loci. The patients-seven women and a 4-year-old boy-exhibited slowly progressive childhood-onset cerebellar gait ataxia associated with cerebellar dysarthria, moderate mental retardation (IQ 62-76), and mild developmental delays in motor acquisition. Nystagmus and pyramidal signs were also observed in some cases. This unique association of clinical features clearly distinguishes this new entity from other previously described ADCA. Cerebral magnetic-resonance imaging showed moderate cerebellar and pontine atrophy in two patients. We performed a genomewide search and found significant evidence for linkage to chromosome 19q13.3-q13.4, in an approximately 8-cM interval between markers D19S219 and D19S553.

See:  http://childnervoussystem.blogspot.com/2016/08/genetic-teasers.html#comment-form 

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