Neonatal vocal cord paralysis-an early presentation of hereditary neuralgic amyotrophy due to a mutation in the SEPT9 gene.

Hereditary neuralgic amyotrophy is a rare autosomal dominant disorder involving recurrent episodes of painful brachial plexus neuropathies. Involvement of other nerves has been described in some families. The age of onset is from infancy to adulthood. Mutations in the SEPT9 gene were identified in approximately half of the hereditary neuralgic amyotrophy families. We evaluated a family with six affected members from three generations with a point mutation in the SEPT9 gene. One of the patients presented in the neonatal period with vocal cord paralysis necessitating intubation and prolonged ventilation. The neonatal presentation of vocal cord paralysis broadens the phenotypic spectrum of hereditary neuralgic amyotrophy. The identification of a SEPT9 mutation in a neonate with respiratory distress due to vocal cord paralysis expands the differential diagnosis in these patients.

NDUFS4 mutations cause Leigh syndrome with predominant brainstem involvement.

Complex I deficiency is a frequent cause of Leigh syndrome. We describe a non-consanguineous Ashkenazi-Sephardic Jewish patient with Leigh syndrome due to complex I deficiency. The clinical and neuroradiological presentation showed predominant brainstem involvement. Blue native polyacrylamide gel electrophoresis analysis revealed an impaired assembly of complex I. The patient was found to be compound heterozygous of two mutations in the NDUFS4 gene: p.Asp119His (a novel mutation) and p.Lys154fs (recently described in an Ashkenazi Jewish family). These findings support the suggestion that the p.Lys154fs mutation in NDUFS4 should be evaluated in Ashkenazi Jewish patients presenting with early onset Leigh syndrome even before enzymatic studies. Our results further demonstrated that NDUFS4 presents a hotspot of mutations in the genetic apparatus of oxidative phosphorylation and the correct assembly of the subunit it encodes is essential for completion of the assembly of complex I.

CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine.

Of the 18 missense mutations in the CACNA1A gene, which are associated with familial hemiplegic migraine type 1 (FHM1), only mutations S218L, R583Q and T666M were identified in more than two independent families. Including the four novel families presented here, of which two represent de novo cases, the R1347Q mutation has now been identified in six families. A genotype-phenotype comparison of R1347Q mutation carriers revealed a wide clinical spectrum ranging from (trauma triggered) hemiplegic migraine with and without ataxia, loss of consciousness and epilepsy. R1347Q is the third most frequent mutation in hemiplegic migraine patients and should therefore be screened with priority for confirmation of clinical diagnosis. This study clearly demonstrates that the availability of multiple families better reflects the full clinical spectrum associated with FHM1 mutations.

A defect in the thymidine kinase 2 gene causing isolated mitochondrial myopathy without mtDNA depletion.

Isolated mitochondrial myopathies (IMM) are either due to primary defects in mtDNA, in nuclear genes that control mtDNA abundance and structure such as thymidine kinase 2 (TK2), or due to CoQ deficiency. Defects in the TK2 gene have been found to be associated with mtDNA depletion attributed to a depleted mitochondrial dNTP pool in non-dividing cells. We report an unusual case of IMM, homozygous for the H90N mutation in the TK2 gene but unlike other cases with the same mutation, does not demonstrate mtDNA depletion. The patient's clinical course is relatively mild and a muscle biopsy showed ragged red muscle fibers with a mild decrease in complexes I and an increase in complexes IV and II activities. This report extends the phenotypic expression of TK2 defects and suggests that all patients who present with an IMM even with normal quantities of mtDNA should be screened for TK2 mutations.

Dysferlinopathy in the Jews of the Caucasus: a frequent mutation in the dysferlin gene.

Dysferlin encoding gene (DYS) is mutated in the autosomal recessive disorders Miyoshi myopathy, Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and distal anterior compartment myopathy, causing dysferlin deficiency in muscle biopsy. Three ethnic clusters have previously been described in Dysferlinopathy: the Libyan Jewish population originating in the area of Tripoli, Italian and Spanish populations. We report another cluster of this muscular dystrophy in Israel among Jews of the Caucasus region. A genomic analysis of the dysferlin coding sequence performed in patients from this ethnic group, who demonstrated an absence of dysferlin expression in muscle biopsy, revealed a homozygous frameshift mutation of G deletion at codon 927 (2779delG) predicting a truncated protein and a complete loss of functional protein. The possible existence of a founder effect is strengthened by our finding of a 4% carrier frequency in this community. These findings are important for genetic counseling and also enable a molecular diagnosis of LGMD2B in Jews of the Caucasus region.

Lack of association of the 3'-UTR polymorphism in the NFKBIA gene with Crohn's disease in an Israeli cohort.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract associated with dysregulation of the immune response. It is caused by a combination of environmental and genetic factors. Patients with CD have a TH1-type inflammatory response characterized by nuclear factor kappa B (NFkappaB) activation. Mutations in the bacterial pattern recognition receptors NOD2/CARD15 and Toll-like receptor 4 (TLR4) genes, which lead to activation of NFkappaB under normal circumstances, have been associated with increased susceptibility for CD. NFkappaB plays a critical role in the immune response and is down-regulated by NFkappaB inhibitor alpha (NFKBIA). NFKBIA was found to be a susceptibility gene for German CD patients lacking NOD2/CARD15 mutations. MATERIALS AND METHODS: A cohort of 231 Israeli CD patients previously genotyped for the single nucleotide polymorphisms (SNPs) in the CARD15, TLR4 susceptibility genes for CD, was analyzed for the 3'-untranslated region (UTR) SNP of the NFKBIA gene in comparison to 100 healthy ethnically matched controls. We evaluated the contribution of the 3'-UTR SNP in NFKBIA in patients with or without other SNPs in CARD15 to age of onset, disease location, and disease behavior (Vienna classification). RESULTS: We did not identify a significant difference in allele and genotype frequencies between either groups or an effect on phenotype. No interactions were found between NFKBIA and any NOD2. CONCLUSIONS: The contribution of population diversity to susceptibility genes for CD plays an important role in disease-associated variants and is important for better understanding of the pathologic mechanisms of the polymorphism.

Fulminant neurological deterioration in a neonate with Leigh syndrome due to a maternally transmitted missense mutation in the mitochondrial ND3 gene.

Leigh syndrome can result from both nuclear and mitochondrial DNA defects. Mutations in complex V genes of the respiratory chain were considered until recently as the most frequent cause for mitochondrial inherited Leigh syndrome, while gene defects in complex I were related to recessive Leigh syndrome. Recently few reports of mutations in the mitochondrial-encoded complex I subunit genes causing Leigh syndrome have been reported. We describe a 1-month-old baby who acutely deteriorated, with abrupt onset of brainstem dysfunction, due to basal ganglia lesions extending to the brainstem. A muscle biopsy demonstrated complex I deficiency. Subsequent analysis of the mitochondrial genome revealed a homoplastic T10191C mutation in the ND3 gene (in blood and muscle), resulting in a substitution of serine to proline. Hair root analysis revealed a 50% mutant load, reflecting heteroplasmy in early embryonic stages. The mutation was also detected in his mother (5%). Western blot analysis revealed a decrease of the 20 kDa subunit (likely ND6) and of the 30 kDa subunit (NDUFA9), which is probably due to instability attributed to the inability to form subcomplexes with ND3. This is the first description of infantile Leigh syndrome due to a maternally transmitted T10191C substitution in ND3 and not due to a de novo mutation. This mutation is age and tissue dependent and therefore may not be amenable to prenatal testing.

A novel missense mutation in the Connexin 26 gene associated with autosomal recessive sensorineural deafness.

Mutations in the Connexin 26 (Cx26) gene (GJB2) are a common cause of hereditary hearing impairment. We report the identification of a novel point mutation in the Cx26 gene, Leu205Pro(L205P), linked to familial, autosomal recessive sensorineural hearing loss. This missense mutation, causing amino acid leucine at position 205 to be substituted by proline, is located in the highly conserved sequence of the fourth transmembrane domain (TM4) of Cx26. Hearing loss with this mutation occurred in a Georgian Jewish family, was congenital, moderate to profound and nonprogressive. We have shown that the new mutation L205P in Cx26 is strongly associated with congenital NSHL. Multiple-sample screening for this mutation can be easily performed with a mismatch PCR that creates a restriction site.

Clinical presentations of mitochondrial cardiomyopathies.

UNLABELLED: To determine the clinical manifestations and interfamilial variability of patients diagnosed with a mitochondrial cardiomyopathy, we reviewed the charts of 14 patients with cardiomyopathy out of 59 patients with mitochondrial disorders who attended the mitochondrial disease clinic at Wolfson Medical Center from 1996 to 2001. All patients underwent a metabolic evaluation including blood lactate, pyruvate, carnitine, and amino acids and urine organic acids. Respiratory chain enzymes were assessed in 10 patients. The mitochondrial DNA (mtDNA) was assessed for mutations. The age at presentation ranged between 6 months and 24 years. Six of the patients died, 5 from heart failure. The cardiomyopathy was hypertrophic in 10 and dilated in 4. Conduction and rhythm abnormalities were present in 6. Eleven patients had family members with mitochondrial disorders. All the patients had additional involvement of one or more systems. Seven patients exhibited a deficiency of a respiratory chain enzyme in the muscle. The MELAS mtDNA point mutation (3243) was found in one patient. Blood lactic acid levels were increased in 5. Brain MRI abnormalities were observed in 4. CONCLUSIONS: Mitochondrial dysfunction frequently affects the heart and may cause both hypertrophic and dilated cardiomyopathy. The cardiomyopathy is usually a part of a multisystem involvement and may rarely be isolated. The course may be stable for many years, but rapid deterioration may occur. Understanding the biochemical and genetic features of these diseases will enable us to comprehend the clinical heterogeneity of these disorders.

Neonatal liver failure and Leigh syndrome possibly due to CoQ-responsive OXPHOS deficiency.

CoQ transfers electrons from complexes I and II of the mitochondrial respiratory chain to complex III. There are very few reports on human CoQ deficiency. The clinical presentation is usually characterized by: epilepsy, muscle weakness, ataxia, cerebellar atrophy, migraine, myogloblinuria and developmental delay. We describe a patient who presented with neonatal liver and pancreatic insufficiency, tyrosinemia and hyperammonemia and later developed sensorineural hearing loss and Leigh syndrome. Liver biopsy revealed markedly reduced complex I+III and II+III. Addition of CoQ to the liver homogenate restored the activities, suggesting CoQ depletion. Histological staining showed prominent bridging; septal fibrosis and widening of portal spaces with prominent mixed inflammatory infiltrate, associated with interface hepatitis, bile duct proliferation with numerous bile plugs. Electron microscopy revealed a large number of mitochondria, which were altered in shape and size, widened and disordered intercristal spaces. This may be the first case of Leigh syndrome with liver and pancreas insufficiency, possibly caused by CoQ responsive oxphos deficiency.

Reversible fulminant lactic acidosis and liver failure in an infant with hepatic cytochrome-c oxidase deficiency.

Cytochrome-c oxidase (COX) is the most common respiratory chain complex involved in liver failure, either as a single enzyme deficiency or as part of multiple enzyme deficiencies. We describe an infant who presented with fulminant lactic acidosis in the neonatal period. The lactic acidosis resolved spontaneously but liver and pancreatic insufficiency ensued. Isolated cytochrome-c oxidase deficiency was found in liver but not in muscle and fibroblasts. mtDNA rearrangements or depletion were ruled out. By the age of one year, liver and pancreatic functions have normalized completely and neurodevelopment is normal.

White matter abnormalities in Leber's hereditary optic neuropathy due to the 3460 mitochondrial DNA mutation.

Leber's hereditary optic neuropathy is a maternally inherited disorder characterized by acute or subacute loss of central vision leading to severe optic atrophy. It is caused by mutations in the mitochondrial genome. Primary mutations are located at nucleotide positions 3460, 11778 and 14484 in genes encoding subunits of complex I of the respiratory chain. The occurrence of a demyelinating disease such as multiple sclerosis has been reported mainly in females with the 11778 mutation. We report a patient with Leber's hereditary optic neuropathy, kyphosis and white matter lesions in association with the 3460 mtDNA mutation. It is suggested that multiple sclerosis-like illness and deformities of the vertebral column may be associated pathogenically with Leber's hereditary optic neuropathy.

Dramatic improvement in mitochondrial cardiomyopathy following treatment with idebenone.

Idebenone, a synthetic analogue of coenzyme Q10, has been shown to improve cardiac function in patients with Friedreich ataxia and a deficiency of respiratory chain complexes I-III. We describe a woman with severe combined right and left heart failure due to a mitochondrial cardiomyopathy. The patient underwent an endomyocardial biopsy as part of an evaluation for cardiac transplantation. It showed severely decreased respiratory complex activities dependent on CoQ, pointing to CoQ depletion. Following idebenone treatment there was a dramatic improvement in her clinical status with resolution of the heart failure.