Prevalence of homozygous deletions of the parkin gene in a cohort of patients with sporadic and familial Parkinson's disease.

Mutation of the parkin gene is a cause of familial Parkinson's disease of the autosomal recessive form; however, its significance in all Parkinson's disease cases is unclear. Deletions in the parkin gene were found in only 2.2% of 184 Japanese patients with Parkinson's disease. However, deletions were present in 25.0% and 40.0% of the patients with juvenile-onset (< 40 y) and with familiality, respectively. On the other hand, deletions were not found in any adult-onset cases (> 40 y). Half of the patients with parkin gene-related Parkinson's disease lacked both heredity and consanguinity.     

Maternally inherited hearing loss in a large kindred with a novel T7511C mutation in the mitochondrial DNA tRNA(Ser(UCN)) gene.

Thirty-six of 43 maternally related members of a large African American family experienced hearing loss. A muscle biopsy specimen from the proband showed cytochrome c oxidase (COX)-deficient fibers but no ragged-red fibers; biochemical analysis showed marked reduction of COX activity. A novel T7511C point mutation in the tRNA(Ser(UCN)) gene was present in almost homoplasmic levels (>95%) in the blood of 18 of 20 family members, and was also found in lower abundance in the other two. Single-fiber PCR showed that the mutational load was greater in COX-deficient muscle fibers. The tRNA(ser(UCN)) gene may be a "hot spot" for mutations associated with maternally transmitted hearing loss.     

Neuropathology of two members of a German-American kindred (Family C) with late onset parkinsonism

We present genealogical and longitudinal clinical observations and autopsy findings of a previously reported kindred, Family C (German-American), with late-onset autosomal dominant parkinsonism with evidence for linkage on chromosome 2p13. The clinical phenotype includes the cardinal features of idiopathic Parkinson's disease. In addition, postural tremor and dementia are detected in some individuals. Two members of the kindred, one affected and one unaffected have recently come to autopsy. The unaffected family member was an 82-year-old woman whose brain showed only mild age-related pathology and no evidence of subclinical Lewy body disease. In contrast, the affected family member was an 83-year-old man whose brain had neuronal loss, gliosis and Lewy bodies in the substantia nigra and other monoaminergic brain stem nuclei, as well as the basal forebrain and amygdala. Lewy bodies and Lewy neurites had a distribution typical of cases of idiopathic Parkinson's disease. Thus, the clinical and pathological findings in this family with autosomal dominant parkinsonism are similar to those of sporadic Parkinson's disease.     

Phenotypic variability in a Spanish family with MNGIE

Clinical, biochemical, and genetic features of a Spanish family with mitochondrial neurogastrointestinal encephalomyopathy are reported. The proband presented with severe gastrointestinal dysmotility and the affected sister had extraocular muscle weakness. In both affected individuals, biochemical defects of thymidine phosphorylase and a pathogenic G-to-A transition mutation at nucleotide 435 in the thymidine phosphorylase gene were identified. The first thymidine phosphorylase mutation identified in Spain showed phenotypic variability at onset.     

Polymorphism in the parkin gene in sporadic Parkinson's disease.

We report polymorphism of the parkin gene in 160 sporadic Parkinson's disease (PD) patients and controls. Three polymorphisms were found: a G-to-A transition in exon 4 (S/N167), a C-to-T transition in exon 10 (R/W366), and a G-to-C transition in exon 10 (V/L380). Genotype distributions and allele frequencies of S/N167 and V/L380 did not differ significantly between the two groups. The R/W366 allele frequency was significantly lower in PD patients (1.2 vs 4.4%). The level of protection from PD provided by this allele was 3.60 (95% CI; range, 0.45-6.50), suggesting that it may be a protective factor against PD.     

New mutation (R42P) of the parkin gene in the ubiquitinlike domain associated with parkinsonism

OBJECTIVE: To investigate the association between parkin gene mutations and parkinsonism in an Italian family in which three of 12 siblings born to first-degree consanguineous parents had early-onset parkinsonism. BACKGROUND: Several deleting or truncating mutations as well as missense mutations of the parkin gene were associated with early-onset parkinsonism. METHOD: Three brothers were examined clinically at several stages of the disease. Single-strand conformational polymorphism analysis was done on the parkin gene of 32 members of the family. Samples showing mobility shifts were considered for mutation analysis. RESULTS: Direct DNA sequencing revealed a novel homozygous amino acid substitution, Arg42Pro, in all three patients compared with a control DNA sample. The mutation occurred in the ubiquitinlike domain at the N-terminal of the protein. The patients did not display the clinical hallmarks previously seen with parkin mutations and were indistinguishable from patients with sporadic PD. CONCLUSIONS: These findings confirm the recessive character of parkin mutations causing early-onset parkinsonism and the essential role of the ubiquitinlike region, highly conserved among species, and in accordance with the proposed parkin function.     

Phenotypic variability in a Spanish family with a Caveolin-3 mutation

We report a Spanish family affected from a late onset, hand-involved and autosomal dominant distal myopathy associated to Caveolin-3 mutation. Signs of muscle hyperexcitability and hyperckemia were observed in the youngest relatives but not motor symptoms.Patients and methodsNeurological examination was performed in all members of the family. Muscle biopsy sample was taken from the proband and DNA genomics was amplified for the two exons of Cav-3 by the polymerase chain reaction (PCR) in all the affected members and in three asymptomatic relatives.ResultsSigns of muscle hyperexcitability and hyperckemia were observed in the affected members from early ages. Cav-3 expression was greatly reduced in the sarcolemma of the proband's muscle. Genetic studies revealed a G → A transition at nucleotide position 80 in exon 1 of the Cav-3 gene (c.80G > A), generating a Arg → Gln change at codon 27 (p.R27Q) of the amino acid chain in heterozygous state, while no mutation was found in unaffected members.ConclusionsSigns of muscle hyperexcitability and hyperckemia at early ages may predict the development of a late onset autosomal dominant hand-involved myopathy associated to Cav-3 mutation in the family reported herein.     

Chronic bilateral subthalamic deep brain stimulation in a patient with homozygous deletion in the parkin gene.

Chronic subthalamic nucleus deep brain stimulation (STN-DBS) is an efficacious treatment for idiopathic Parkinson's disease (PD) that cannot be further improved by medical therapy. We present a case of an individual with juvenile parkinsonism caused by homozygous deletion of exon 3 in the parkin gene with disabling long-term side-effects from levodopa who underwent bilateral STN neuromodulation. Parkin-linked parkinsonism may show clinical features different from sporadic PD, yet it shares levodopa responsiveness. Because levodopa responsiveness is a predictor of STN-DBS efficacy, we argued that this kind of surgical approach might be efficacious in hereditary parkin-linked juvenile parkinsonism. We evaluated clinical and functional assessment before and 12 months after surgery. The results showed that the Unified Parkinson Disease Rating Scales Motor score improved by 84% in our patient, the levodopa equivalent daily dose medication (LEDD) was reduced by 66%, and, finally, disabling and severe dyskinesias disappeared.     

Large deletions of the PROS1 gene in a large fraction of mutation-negative patients with protein S deficiency

Protein S deficiency is an autosomal dominant disorder that results from mutations in the PROS1 gene. Conventional mutation detection techniques fail to detect a pathogenic PROS1 mutation in approximately 50% of cases.The present study investigates whether large deletions of PROS1 are found in families where mutations in the PROS1 gene have not been found despite sequencing. For this purpose,a dense set of SNP and microsatellite markers were used in segregation analysis to identify deletions. Large deletions were identified by this technique in three out of eight investigated families (38%).The deletions encompassed at least 35 kb, 437 kb and 449 kb respectively. The deletions were confirmed by quantitative PCR. Haplotype analysis showed that the three large deletions and the five other disease haplotypes were all different. All of the eight disease haplotypes co-segregated with protein S deficiency, but each of the five non-deletion haplotypes were present also in normal individuals. In conclusion: Large deletions of PROS1 are relatively common in protein S deficiency patients and screening for large deletions in PROS1 mutation-negative individuals are therefore warranted.     

A clinical study of a large inbred kindred with pure familial spastic paraplegia.

BACKGROUND AND OBJECTIVES: Spastic paraplegia, an uncommon neurodegenerative disorder with phenotypic and genotypic heterogeneity, is mainly characterized by progressive weakness and spasticity of the lower limbs. We here present a large inbred family with pure familial spastic paraplegia outlining the clinical picture, the age at onset and the possible mode of inheritance. METHODS: This family was ascertained through two probands after which we structured an extended 10 generation pedigree. We examined 43 available family members to identify affected individuals based on fixed criteria. The clinical presentation and phenotypic specifics of this disease were studied in the affected members. We analyzed the possible mode of inheritance and the age at onset in this family. RESULTS: This 10 generation family reported about 50 affected individuals distributed over 5 consecutive generations. We identified 13 affected individuals out of the examined 43 and five individuals were classified as probably affected. We noticed the clinical specifics of this disorder in this family and identified some unique features not described in previous reports. DISCUSSION AND CONCLUSION: The mode of inheritance is either autosomal recessive or autosomal dominant with incomplete penetrance or variable expression of the age at onset. The age at onset seems to decrease with successive generations, either due to a true anticipatory phenomenon or to increased awareness. The unique features of this disorder in this family are discussed.     

Alzheimer's disease: a model from the quantitative study of a large kindred.

In an Italian kindred (family N), early onset Alzheimer's disease has been transmitted in a Mendelian autosomal fashion since the early 18th century. The age at death of affected members of the family varies widely, and was taken as an index of the age of expression, a measure of phenotypic variability. Either a gamma or a log-normal algorithm provides the best fit for the age at death distribution. Subsets of family N widely different as to time and place have the same age at death of patients: Environment appears to play a negligible role in the expression of disease. Pairwise correlation between an affected parent and child is zero: The disease is monogenic (no major expression gene). The same stochastic distribution of age of expression, but with late onset, and after correction for death from other causes, is compatible with the epidemiology of Alzheimer's disease in general. Mendelian genetics is a possible model for Alzheimer's disease etiology.     

A large German kindred with cold-aggravated myotonia and a heterozygous A1481D mutation in the SCN4A gene

Muscle sodium-channel disorders cover a spectrum of rare myotonic diseases. In a German family with 17 affected individuals in four generations, we identified a heterozygous missense mutation in exon 24 A1481D (c.4442 C>A) of the voltage-gated sodium channel gene (SCN4A) alpha subunit. Phenotypes of 12 family members were characterized by a mild myotonia with cold sensitivity but without paramyotonia. The index patient presented with fluctuating cold- and exercise-induced stiffness of ocular, facial, and distal muscles. The myotonia became more severe at the age of 22 years. His father had had cold- and exercise-induced periodic weakness with fluctuating myotonia since age 10. Later he developed a more severe, purely exercise- and cold-aggravated myotonia of arms, hands, and facial muscles. The father's mother presented with cold-induced myotonia until age 65, when progressive weakness of proximal limb muscles developed. Her muscle biopsies revealed considerable myopathic changes with a variety of fine structural alterations. This study presents a family with cold-aggravated myotonia and progression of myopathic changes in the muscle biopsy with increasing age. In older patients, sodium channelopathies may mimic the phenotypic features of myotonic dystrophy type 2.