Bowel obstruction in patients with Alpers-Huttenlocher syndrome.

Alpers-Huttenlocher syndrome (AHS) is a very rare autosomal recessive disorder. AHS is caused by homozygous or compound heterozygous mutations in the nuclear gene encoding mitochondrial DNA polymerase gamma (POLG, chromosome 15q25). Most patients become symptomatic before the age of 2 years. We report 3 patients who were treated in our clinic between 2007 and 2010. All patients suffered from myoclonic seizures and had at least one refractory convulsive status which led to the diagnosis. All of them had varying degrees of developmental delay, 2 of them additionally ataxia. Gastrointestinal motility problems were severe in all patients despite only mildly deranged liver function. While in most aspects our patients present with typical AHS features, they also share intestinal problems, a feature that has not been recognized as typical for AHS before. AHS is a multisystem disorder that does affect all cell systems. Liver and brain are organs with the highest energy demand and are therefore usually affected early in the disease course of AHS. However, constipation and bowel obstruction should be regarded as typical complications in AHS and patients should be monitored and treated to improve quality of life. Regarding treatment options for epilepsy in AHS ketogenic diet as well as lacosamide might be considered.

Spinocerebellar ataxia type 4 (SCA4): Initial pathoanatomical study reveals widespread cerebellar and brainstem degeneration.

Spinocerebellar ataxia type 4 (SCA4), also known as 'hereditary ataxia with sensory neuropathy', represents a very rare, progressive and untreatable form of an autosomal dominant inherited cerebellar ataxia (ADCA). Due to a lack of autopsy cases, no neuropathological or clinicopathological studies had yet been performed in SCA4. In the present study, the first available cerebellar and brainstem tissue of a clinically diagnosed and genetically-confirmed German SCA4 patient was pathoanatomically studied using serial thick sections. During this systematic postmortem investigation, along with an obvious demyelinization of cerebellar and brainstem fiber tracts we observed widespread cerebellar and brainstem neurodegeneration with marked neuronal loss in the substantia nigra and ventral tegmental area, central raphe and pontine nuclei, all auditory brainstem nuclei, in the abducens, principal trigeminal, spinal trigeminal, facial, superior vestibular, medial vestibular, interstitial vestibular, dorsal motor vagal, hypoglossal, and prepositus hypoglossal nuclei, as well as in the nucleus raphe interpositus, all dorsal column nuclei, and in the principal and medial subnuclei of the inferior olive. Severe neuronal loss was seen in the Purkinje cell layer of the cerebellum, in the cerebellar fastigial nucleus, in the red, trochlear, lateral vestibular, and lateral reticular nuclei, the reticulotegmental nucleus of the pons, and the nucleus of Roller. In addition, immunocytochemical analysis using the anti-polyglutamine antibody 1C2 failed to detect any polyglutamine-related immunoreactivity in the central nervous regions of this SCA4 patient studied. In view of the known functional role of affected nuclei and related fiber tracts, the present findings not only offer explanations for the well-known disease symptoms of SCA4 patients (i.e. ataxic symptoms, dysarthria and somatosensory deficits), but for the first time help to explain why diplopia, gaze-evoked nystagmus, auditory impairments and pathologically altered brainstem auditory evoked potentials, saccadic smooth pursuits, impaired somatosensory functions in the face, and dysphagia may occur during the course of SCA4. Finally, the results of our immunocytochemical studies support the concept that SCA4 is not a member of the CAG-repeat or polyglutamine diseases.

Spinocerebellar ataxia type 4. Investigation of 34 candidate genes.

The spinocerebellar ataxias (SCAs) with autosomal dominant inheritance are a clinically and genetically heterogeneous group of neurodegenerative disorders. To date 24 different loci have been identified for these conditions. A locus at chromosome 16q22.1 co-segregates with the disease phenotype in families of Scandinavian, Japanese and German origin. The corresponding SCA4 locus was narrowed down to 7.94 Mb for the two European and to 1.25 Mb for Japanese pedigrees. Unfortunately, because of the phenotypic differences between patients from Japan and Europe it is not possible to decide if SCA families linked to chromosome 16q22.1 share a common disease genotype or not. To look for mutations in the German family we screened 34 candidate genes in a 3.69 cM region. With the exception of two cSNPs, no segregation of DNA variations with the disease phenotype was found.

Extension of the mutation spectrum in Friedreich's ataxia: detection of an exon deletion and novel missense mutations.

Friedreich's ataxia (FRDA), the most common autosomal recessively inherited ataxia, is due to a homozygous GAA triplet repeat expansion in the first intron of the FRDA gene in about 96% of patients. Approximately 4% of FRDA patients are compound heterozygotes with a GAA repeat expansion in one allele and a point mutation in the coding region of the second allele. To reinvestigate the mutation spectrum, we searched for mutations including exon deletions in six patients heterozygous for the GAA repeat expansion and found two unknown missense mutations, p.Asn146Lys and p.Leu186Arg, in trans to the expanded FRDA allele. Interestingly, we detected a heterozygous 2776 bp deletion including exon 5a in one of our patients. This deletion removes 50 of the 210 residues of the frataxin. Furthermore, since no FRDA case with two-point mutations is known, we screened eight patients with FRDA phenotype but GAA alleles within the normal range but did not reveal a mutation within the FRDA gene. In addition, DNA polymorphisms have been found in four out of 100 control individuals in this study.

Spinocerebellar ataxia type 5: clinical and molecular genetic features of a German kindred.

The authors report a German family with autosomal dominant cerebellar ataxia tightly linked to the spinocerebellar ataxia type 5 (SCA5) locus (multipoint lod score 5.76). The phenotype is characterized by a purely cerebellar syndrome with a downbeat nystagmus occurring prior to the development of other features. Imaging studies demonstrated cortical cerebellar atrophy. Progression is slow even in patients with a disease onset during the second decade. The age at onset varies from 15 to 50 years.

Refinement of the spinocerebellar ataxia type 4 locus in a large German family and exclusion of CAG repeat expansions in this region.

Spinocerebellar ataxia type 4 (SCA4) is an autosomal dominant disorder mapped to chromosome 16q22.1 in a large Utah kindred. The clinical phenotype is characterized by cerebellar ataxia with sensory neuropathy. We describe a five-generation family from northern Germany with similar clinical findings linked to the same locus. Haplotype analyses refined the gene locus to a 3.69 cM interval between D16S3019 and D16S512. Analysis of nine CAG/CTG tracts in this region revealed no evidence for a repeat expansion.

R124C mutation of the betaIGH3 gene leads to remarkable phenotypic variability in a Greek four-generation family with lattice corneal dystrophy type 1.

Five autosomal dominantly inherited corneal dystrophies are caused by missense mutations in the betaIGH3 gene on chromosome 5q31. Here we describe the clinical features and the analysis of the betaIGH3 gene in a Greek four-generation family with lattice corneal dystrophy type 1 (CDL1). Sequencing of the betaIGH3 cDNA from an affected family member revealed the R124C mutation. More recent data indicate that this is probably a mutation hot spot in CDL1. We could not find a common haplotype with another CDL1 family with the R124C mutation demonstrating that this mutation occurs independently in different families. The clinical course of the disease showed a remarkable variability between the affected family members. To investigate a possible role between the phenotypic variability and apolipoprotein E (ApoE), which co-localises with amyloid deposits in CDL1, we determined the ApoE genotype of all family members. The resulting data revealed no association with the variable clinical course.

Different types of repeat expansion in the TATA-binding protein gene are associated with a new form of inherited ataxia.

A novel neurological syndrome has recently been described to be associated with an expanded polyglutamine domain. The expansion results from partial duplication within the TATA-binding protein (TBP). By investigation of 604 sporadic and familial cases with various forms of neurological syndromes and 157 unaffected individuals, we found repeat expansions in the TBP in four patients of two families with autosomal dominant inheritance of ataxia, dystonia, and intellectual decline. Two different genotypes for the repetitive sequence could be demonstrated which led to elongated polyglutamine stretches between 50 and 55 residues, whereas normal alleles with 27 to a maximum of 44 glutamine residues were found in this study. The expansion to 50 or more glutamine residues results in a pathological phenotype and confirms the report of a new polyglutamine disease.

Limited somatic mosaicism for Friedreich's ataxia GAA triplet repeat expansions identified by small pool PCR in blood leukocytes.

OBJECTIVES: Friedreich's ataxia (FRDA), the most common inherited ataxia, is associated with an unstable expansion of GAA repeats in the first intron of the frataxin gene on chromosome 9. We investigated the mosaicism of expanded alleles to elucidate the basis for genotype phenotype correlations. PATIENTS AND METHODS: We studied the instability of the GAA repeat in blood leukocytes from 45 individuals including 20 FRDA patients and 20 non-affected controls using small pool PCR combined with Southern blotting and hybridization. RESULTS: Expanded GAA repeats could be resolved into distinct alleles showing differences in length up to 1,000 triplets for an individual genome. We found a significant correlation between the size of the largest allele and the range of mosaicism. CONCLUSION: The somatic mosaicism for expanded repeats observed in FRDA patients rendered the precise measurement of allele sizes more difficult and may influence the results of studies correlating the clinical spectrum with the genotype. Following, a confidential prediction of the prognosis deduced from the repeat length is hardly possible for an individual FRDA patient.

CAG repeat analyses in frozen and formalin-fixed tissues following primer extension preamplification for evaluation of mitotic instability of expanded SCA1 alleles.

Neurodegenerative disorders, including spin-ocerebellar ataxias (SCA), Huntington disease (HD) and dentatorubral-pallidoluysian atrophy (DRPLA), are associated with unstable CAG repeats. To investigate the mitotic stability of the repetitive element in the genes for SCA1, SCA3, HD, and DRPLA we extracted DNA from up to 13 tissue samples from four deceased individuals with progressive neurological disorders and neuropathological signs. Due to the formalin fixation of some tissues the genomic DNA was highly degraded and unsuitable for amplification of fragments longer than 150 bp. After size selection and primer extension preamplification, specific analyses could be performed even for expanded alleles. In all four patients the SCA1 mutation could be demonstrated, in one case with remarkable somatic heterogeneity of the elongated allele, whereas alleles of the normal range were stable in all tissues examined.