Characterization of DCTN1 genetic variability in neurodegeneration.

OBJECTIVE: Recently, mutations in DCTN1 were found to cause Perry syndrome, a parkinsonian disorder with TDP-43-positive pathology. Previously, mutations in DCTN1 were identified in a family with lower motor neuron disease, in amyotrophic lateral sclerosis (ALS), and in a family with ALS/frontotemporal dementia (FTD), suggesting a central role for DCTN1 in neurodegeneration. METHODS: In this study we sequenced all DCTN1 exons and exon-intron boundaries in 286 samples diagnosed with Parkinson disease (PD), frontotemporal lobar degeneration (FTLD), or ALS. RESULTS: This analysis revealed 36 novel variants (9 missense, 5 silent, and 22 noncoding). Segregation analysis in families and association studies in PD, FTLD, and ALS case-control series did not identify any variants segregating with disease or associated with increased disease risk. CONCLUSIONS: This study suggests that pathogenic mutations in DCTN1 are rare and do not play a common role in the development of Parkinson disease, frontotemporal lobar degeneration, or amyotrophic lateral sclerosis.

Unilateral pallidotomy for Parkinson's disease: comparison of outcome in younger versus elderly patients.

We studied the effects of medial pallidotomy in the first 20 consecutive patients with Parkinson's disease (PD) undergoing this MRI/electrophysiologically guided procedure at our institution. The mean age of patients was 65.5 years (median 66.5) and none suffered any serious complications. Pallidotomy significantly improved motor function in both "on" and "off" states as measured by Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and timed tests (Purdue pegboard and counter tapping) in the arm contralateral to surgery 3 months postoperatively. Patients also improved in terms of activities of daily living, reflected by improved UPDRS activity of daily living and complications of therapy scoring and reduced levodopa-induced dyskinesias; six of 11 patients who could not walk in an "off" state prior to surgery could do so postoperatively. The total UPDRS score improved by 22% from preoperative values. The aforementioned improvements occurred similarly in patients greater than (n = 11) or less than 65 years (n = 9) at surgery. Neuropsychological measures indicated that although the majority of cognitive function remains unchanged in right-handed PD patients following dominant (left) hemisphere pallidotomy, mild specific declines in word generation are present. The findings of this study suggest that unilateral pallidotomy is safe and associated with improved motor functioning in elderly as well as younger PD patients experiencing significant disability despite optimal medical therapy.

Characterization of cDNA and genomic DNA encoding SERCA1, the Ca(2+)-ATPase of human fast-twitch skeletal muscle sarcoplasmic reticulum, and its elimination as a candidate gene for Brody disease.

Genomic DNA and cDNA encoding human SERCA1, the Ca(2+)-ATPase of fast-twitch skeletal muscle sarcoplasmic reticulum (the ATP2A1 gene on chromosome 16p12), were isolated and characterized. The cDNA encodes 994 amino acids. The genomic DNA is 26 kb long and contains 23 exons, one of which can be alternatively spliced. The locations of each of the exon/intron boundaries are the same as those previously identified in the rabbit ATP2A1 gene. Brody disease is an inherited disorder of skeletal muscle, characterized by exercise-induced impairment of muscle relaxation. It has been postulated to result from a deficiency in SERCA1. In a search for the genetic basis of Brody disease, the coding sequence of the ATP2A1 gene in one Brody patient and the full-length sequences of two SERCA1 cDNAs in two other, unrelated Brody patients were compared with normal ATP2A1 sequences. In all three cases, the coding and splice junction sequences were normal, indicating that the forms of Brody disease manifested in these three patients are not caused by mutations in the coding or splice junction regions of the ATP2A1 gene.

Primary adhalin deficiency as a cause of muscular dystrophy in patients with normal dystrophin.

In our experience, more than half of muscular dystrophy patients show a primary dystrophinopathy. The underlying cause of muscular dystrophy in the vast majority of patients with normal dystrophin is unknown. Recently, a French family with 4 young siblings showing a muscular dystrophy of unknown progression was shown to have a primary deficiency of "adhalin," the 50-kd dystrophin-associated protein. Here we report the screening of the entire adhalin coding sequence in muscle biopsy specimens from 30 muscular dystrophy patients to (1) determine whether adhalin deficiency is restricted to the French population, (2) determine the incidence of adhalin deficiency in muscular dystrophy patients, and (3) characterize the clinical features and mutations in adhalin-deficient patients. We identified a single African-American girl with childhood-onset muscular dystrophy and adhalin gene mutations. We found her to be a compound heterozygote for two different mutations of the same amino acid (Arg98Cys; Arg98His), one of which was previously identified in the French family. Our results suggest that primary adhalin deficiency in patients with muscular dystrophy but normal dystrophin is relatively infrequent, and that adhalin-deficient patients are not restricted to the French population.

Autosomal dominant distal spinal muscular atrophy in four generations.

Distal spinal muscular atrophy is a rare lower motor neuron disorder that may be difficult to distinguish clinically from type II Charcot-Marie-Tooth disease. We report on clinical and pathologic findings in 13 members of a four-generation extended family with autosomal dominant distal spinal muscular atrophy. The patients developed a slowly progressive lower motor neuron disorder involving mainly the distal lower extremities; onset was from the second to fourth decades. Electromyography and muscle biopsy findings were indicative of motor denervation. Combined silver/cholinesterase/immunocytochemical staining of intramuscular nerve revealed abundant collateral axonal branching in mild disease but marked loss of terminal motor endplate innervation in the more severe state, suggesting decreased growth of motor axon collaterals with disease progression. Multipoint DNA linkage analysis showed that this family's disorder is not linked to the chromosome 5q11.2-13.3 spinal muscular atrophy locus.

Conjugal amyotrophic lateral sclerosis: report of a young married couple.

We report a 38-year-old nurse who developed amyotrophic lateral sclerosis (ALS) beginning in September 1990. In May 1991, her 38-year-old husband developed dysarthria, which progressed to typical ALS. This is the fourth report in the literature of conjugal ALS occurring outside of Guam. Although this event is most likely due to coincidence, exogenous agents should be considered in the etiology of ALS.

Werdnig-Hoffmann disease and chronic distal spinal muscular atrophy with apparent autosomal dominant inheritance.

We report on a family in which both Werdnig-Hoffmann disease (severe infantile-onset spinal muscular atrophy) and chronic distal spinal muscular atrophy occurred, with apparent autosomal dominant inheritance. The female proband clinically had Werdnig-Hoffmann disease and died at 10 months. In their second decade of life, the proband's father and his 2 brothers developed bilateral progressive atrophy and weakness of the hands and mild weakness in the distal parts of the legs. Their mother had no symptoms or signs of motor neuron disease but electromyography revealed distal denervation of the limbs. While the family studies suggest autosomal dominant inheritance, it is possible that the proband's condition was influenced by a maternally derived allelic or modifying trait.

Congenital hypomyelination neuropathy with arthrogryposis multiplex congenita.

A term male infant is described with an isolated disorder of peripheral myelination. At necropsy, the great majority of medium-to-large axons were unmyelinated. Electron microscopy showed normal axons and redundant lamination of basement membrane, suggestive of early onion bulb pathology. Immunohistochemistry of peripheral nerve showed deficiency of the myelin proteins P2 and P0, myelin basic protein, and myelin-associated glycoprotein. Arrest of peripheral myelination at the promyelin stage appears to be the origin of myelin deficiency.

Progressive dystonia following resuscitation from cardiac arrest.

We report a case of a 55-year-old man in whom progressive extrapyramidal disease developed nearly 1 year after resuscitation from cardiopulmonary arrest. Parkinsonian features evolved within 3 months, and progressive generalized dystonia developed after 11 months. CT and MRI revealed bilateral basal ganglia infarction. Autopsy after 4 years of illness showed bilateral basal ganglia necrosis with preserved corticospinal tracts. These findings support earlier suggestions that postinfarction dystonia is mediated by a pyramidal system lacking normal striatal control.

DNA length polymorphism 5' to the myelin basic protein gene is associated with multiple sclerosis.

A site of DNA polymorphism linked to the myelin basic protein gene, identified as restriction fragment length polymorphism, was analyzed in a population-based study comparing patients with clinically definite multiple sclerosis (MS) and population-matched control subjects. A 0.9-kilobase (kb) genomic DNA fragment (EcoG) encompassing the first exon of the human myelin basic protein gene, located on the long arm of chromosome 18, identified ten alleles arising from a region of DNA, 1.5 kb 5' to the myelin basic protein gene first exon coding region. Produced by RsaI digests and ranging in length from 2.05 to 2.15 kb, these alleles vary in size by up to 100 base pairs due to insertion or deletion, or both, from a 1-kb length of repetitive DNA. Allele frequencies among 65 patients with MS were compared with those of 63 control subjects. Chi square for these data was significant (p less than 0.001), largely due to a preponderance in the patients with MS of alleles in the 2.14- to 2.15-kb range. Comparison of the numbers of patients with MS and control subjects bearing specific alleles showed that 45% of the patients carried at least one allele of 2.14 to 2.15 kb as opposed to 19% of control subjects (p less than 0.005). These data, while preliminary, suggest that patients with MS differ from population-matched control subjects with respect to DNA polymorphism linked to the myelin basic protein gene. Although no pathogenic relationship between this polymorphism and MS can be presupposed, this finding raises the possibility that the myelin basic protein gene or some other myelin basic protein-linked locus may be a factor in susceptibility to MS.

Repetitive DNA (TGGA)n 5' to the human myelin basic protein gene: a new form of oligonucleotide repetitive sequence showing length polymorphism.

DNA 5' to the human myelin basic protein (MBP) gene, mapped to 18q22----qter, is known to manifest multiallelic DNA length variation with heterozygosity of at least 45%. Isolation of genomic DNA containing the MBP gene first exon and its 5' flanking region reveals that this polymorphism arises from a 994-bp region of the diverged tandem repeat (TGGA)249. This sequence is located from 1082 to 2075 bp upstream of the MBP initiator methionine. The repetitive sequence is 18% diverged from (TGGA)249 and from analysis of higher order subsequence reiterations appears to have undergone extensive recombination. The pattern of higher order repetition suggests that multiple crossover and gene conversion events have occurred within a 1.0-kb region. Molecular clones of this sequence represent essentially the longest allelic form of this region seen in Southern transfer analysis. This repetitive DNA is similar to a sequence 5' to the human myoglobin gene.

DNA length polymorphism located 5' to the human myelin basic protein gene.

A region of DNA 5' to the human myelin basic protein (MBP) gene, located on the long arm of chromosome 18, is a site of restriction-fragment-length polymorphism (RFLP) showing 37% heterozygosity in 40 subjects studied. Southern transfer analysis using a 0.9-kb genomic fragment encompassing the first exon of the human MBP gene reveals this polymorphism with at least nine restriction enzymes, indicating that insertion, deletion, or both is the basis for the DNA length variation. Double restriction-enzyme digest analysis suggests that this polymorphism is within the region 0.5-2.0 kb upstream of the coding region of the first exon of the human MBP gene. Eleven different allelic RFLPs were identified, differing in size by as many as 450 bp. The distribution of insertion/deletion-size variants from this region is bimodal, with most restriction fragments varying in size over a 0.1-kb range. Pedigree analysis of polymorphism at this site in one three-generation family shows Mendelian assortment of parental haplotypes. The form and frequency of polymorphism generated by this site is similar to that reported for human DNA regions comprised of homologous short tandem repeats.