Early-onset ophthalmoplegia in Leigh-like syndrome due to NDUFV1 mutations

Mitochondrial disorders can be linked to mutations in both mitochondrial and nuclear deoxyribonucleic acid, corresponding to various clinical phenotypes. Mutations in nuclear genes, including NDUFV1, have been associated with severe encephalomyopathies in infants, but genotype-phenotype correlations have remained elusive. This report details the complete clinical, biochemical, and molecular data of a 7-year-old male who presented at the age of 7 months with progressive ophthalmoplegia and later developed cerebellar ataxia, spasticity, and dystonia. Complex I deficiency was demonstrated in muscle, and two pathogenic missense mutations were present in the NDUFV1 gene. Ketogenic diet has seemingly improved the oculomotor palsy but has been unable to correct other neurologic symptoms. Considering other cases from the literature, this report broadens our understanding of genotype-phenotype correlations for NDUFV1 mutations and illustrates a potential and partial efficacy of ketogenic diet in complex I deficient patients.     

Clinical and molecular features of adPEO due to mutations in the Twinkle gene

We have analyzed Twinkle, the causative gene for autosomal dominant progressive external ophthalmoplegia (adPEO) on chromosome 10, in 11 Australian autosomal dominant progressive external ophthalmoplegia families of Caucasian origin, and investigated whether there are distinct molecular and clinical features associated with mutations in this gene. We found two new mutations in Twinkle, in 3 of the 11 pedigrees examined. One resides in the linker region of this gene while the other is in the primase domain. Both regions are highly conserved between species. Multiple deletions in the mtDNA from muscle are not always prominent and there are significant variations in the clinical presentation within and between families with mutations in the Twinkle gene. Therefore, genotype/phenotype predictions are difficult. No mutations were found in adenine nucleotide translocator 1 (ANT1), another known adPEO causative gene, in four of the seven remaining families investigated. Thus, Twinkle appears to be the most common gene associated with adPEO in Australian families.     

Congenital muscle fiber-type disproportion in a patient with congenital central hypoventilation syndrome due to PHOX2B mutations

Increasing numbers of genetic origins are being reported for congenital muscle fiber-type disproportion. Most of these identified disorders are genetic myopathies. This is the first case report (to our knowledge) demonstrating congenital central hypoventilation syndrome due to PHOX2B mutations with congenital muscle fiber-type disproportion. The muscle histopathologic findings in the patient showed no changes of disuse atrophy and suggest that PHOX2B mutations may have an additional role in muscle development, contributing to respiratory failure in congenital central hypoventilation syndrome.     

High-frequency rhythmic cortical myoclonus in a long-surviving patient with nonketotic hypergylcemia

An 11-year-old girl with nonketotic hyperglycinemia who typically presented with a picture of early myoclonic encephalopathy in the neonatal period is presented in this article. Treated early with sodium benzoate and dextromethorphan, she became seizure-free, while myoclonus persisted. During examination, multifocal rhythmic myoclonic jerks in gamma frequency enhanced by motor activity were noted. Coherence analysis of the electroencephalography-electromyography relationship indicated a cortical origin of the myoclonic jerks. Observation of this case suggests that rhythmic cortical myoclonus may represent a late evolution of this rare disorder.     

Periodic myoclonus due to cytomegalovirus encephalitis in a patient with good syndrome

BACKGROUND: Good syndrome (GS) refers to a constellation of thymoma and adult-onset immunodeficiency characterized by low or absent B cells, hypogammaglobulinemia, and variable defects in cell-mediated immunity with an inverted CD4/CD8(+) T-cell ratio. Patients may develop severe or chronic infections as a result of this immunodeficiency. OBJECTIVE: To describe a patient with GS who developed cytomegalovirus (CMV) encephalitis and showed a periodic electroencephalographic pattern and myoclonus. DESIGN: Case report. SETTING: Outpatient neurology clinic at a university medical center. Patient A 64-year-old man who developed periodic myoclonus involving the right half of his body and the left arm. RESULTS: Five years previously, the patient had undergone resection of a pathologically confirmed epithelial thymoma. Quantitative CMV polymerase chain reaction of the serum and cerebrospinal fluid showed strongly positive results (1:10 000), allowing the diagnosis of CMV encephalitis. CONCLUSIONS: To the best of our knowledge, myoclonus and periodic electroencephalographic pattern have not previously been reported in CMV encephalitis. Opportunistic CMV infection should be considered early in the evaluation of patients with GS or a history of thymoma who develop unusual neurological symptoms.     

Parkin mutations in a patient with hemiparkinsonism-hemiatrophy: a clinical-genetic and PET study

The authors describe a 37-year-old woman with early-onset hemiparkinsonism (HP) and ipsilateral body hemiatrophy (HA). Genetic analysis revealed a missense mutation (Arg275Trp) and a duplication of exon 7 of parkin. The complementary metabolic and receptor pattern of PET ligands corresponded to that typically found in idiopathic PD, although tracer binding asymmetry was lacking. Parkin mutations should be considered in HPHA, particularly when there is a younger age at onset and dystonia is an early sign.     

Three novel SURF-1 mutations in Japanese patients with Leigh syndrome

Leigh syndrome, a severe neurodegenerative disorder, commonly is associated with cytochrome c oxidase deficiency. Recent studies in white patients indicate that SURF-1 gene mutations can cause Leigh syndrome associated with cytochrome c oxidase deficiency. When we measured cytochrome c oxidase activity in cultured lymphoblastoid cells from our Japanese patients with typical Leigh syndrome, three patients demonstrated cytochrome c oxidase deficiency. Three novel mutations of the SURF-1 gene were identified in two of these three patients with cytochrome c oxidase deficiency. All mutations predicted loss of function of the SURF-1 protein; in both patients' cells, cytochrome c oxidase activity was decreased to less than 20% of the control mean. These results indicate that cultured lymphoblastoid cells are useful for elucidating the etiology of Leigh syndrome, and that loss of function of the SURF-1 gene product can be responsible for Leigh syndrome associated with severe cytochrome c oxidase deficiency in Japanese patients.     

Rubral lateropulsion due to vertebral artery dissection in a patient with Klippel-Feil syndrome

BACKGROUND: Neurologic deficits in patients with Klippel-Feil syndrome usually are attributed to direct compression of neuronal structures or hypoperfusion secondary to compression of the vertebral arteries by bony abnormalities. OBJECTIVE: To describe a 38-year-old woman with known Klippel-Feil syndrome who developed lateropulsion. RESULTS: The results of magnetic resonance imaging were consistent with rubrothalamic stroke. The cerebral angiogram confirmed vertebral artery dissection at the level of her previously observed bony abnormality. CONCLUSIONS: Hypermobility adjacent to fused vertebrae subjects the vertebral artery to increased shear forces. Thus, Klippel-Feil syndrome may be a predisposing factor for vertebral artery dissection. Moreover, to our knowledge, this case represents the second known case of rubral lateropulsion.     

Clinical variability of early-onset congenital myasthenic syndrome due to biallelic RAPSN mutations in Brazil

Mutations in RAPSN are an important cause of congenital myasthenic syndrome (CMS), leading to endplate acetylcholine receptor deficiency. We present three RAPSN early-onset CMS patients (from a Brazilian cohort of 61 CMS patients). Patient 1 and patient 2 harbor the mutation p.N88K in homozygosity, while patient 3 harbors p.N88K in compound heterozygosity with another pathogenic variant (p.V165M; c.493G ≥ A). At onset, patient 3 presented with more severe symptoms compared to the other two, showing generalized weakness and repeated episodes of respiratory failure in the first years of life. During adolescence, she became gradually less symptomatic and does not require medication anymore, presenting better long-term outcomes than patients 1 and 2. This case series illustrates the variability of RAPSN early-onset CMS, with patient 3, despite severe onset, revealing an almost complete reversal of myasthenic symptoms, not limited to apneic episodes. Moreover, it suggests that RAPSN CMS may be underdiagnosed in non-European countries.     

Usefulness of diagnostic tools in a GLUT1 deficiency syndrome patient with 2 inherited mutations

In some patients with GLUT1 deficiency syndrome (GLUT1-DS), the diagnosis can be difficult to reach. We report a child with 2 inherited mutations suggesting an autosomal recessive transmission of SLC2A1 mutations.MethodsThe child and her parents were explored with erythrocyte 3-O-methyl-d-Glucose uptake, glucose uptake in oocytes expressing GLUT1 with the gene mutations and measure of the expression of GLUT1 at the surface of the circulating red blood cells by flow cytometry (METAglut1™ test).ResultsBoth erythrocyte glucose uptake and glucose uptake in oocyte with the patient’s mutations did not support the diagnosis of a mild GLUT1-DS phenotype with autosomal recessive transmission of SLC2A1 mutations. Instead, GLUT-1 expression at the surface of the erythrocytes appeared to better correlate with the clinical phenotypes in this family.ConclusionThe diagnostic value of these functional/expression tools need to be further studied with a focus on mild phenotype of GLUT1-DS.     

Early Onset Parkinson's disease due to DJ1 mutations: An Indian study

IntroductionEarly Onset Parkinson's Disease (EOPD) is genetically heterogeneous. PARK2 mutations are the commonest cause of autosomal recessive EOPD followed by PINK1.DJ1 mutations is rare and there is scarce literature on its phenotype and long term outcome.ObjectivesWe undertook a retrospective study to determine the prevalence of DJ1 mutation(s) in an Indian population and describe the clinical features and long term outcome of EOPD patients with these mutations.MethodsOne hundred EOPD patients and 114 controls were evaluated. All the seven coding exons of DJ1 gene were screened for novel and reported mutations by PCR- Sanger sequencing.ResultsA novel homozygous missense mutation (c.313 A > T, p. Ile105Phe) in exon 5 was seen in one patient and four unrelated patients had a homozygous missense single nucleotide variant rs71653619 (c.293 G > A, p.Arg98Gln). The clinical phenotype comprised of asymmetrical onset, slowly progressive Parkinsonism with levodopa induced motor restlessness in a patient with the novel mutation (c.313 A > T, p. Ile105Phe) while subjects with c.293 G > A, p.Arg98Gln had early onset levodopa responsive symmetrical Parkinsonism.ConclusionDJ1 mutations account for ∼5% of EOPD patients from the Indian population. This study further adds to the clinical spectrum of EOPD with DJ1 mutations.     

Clinical and molecular characterisation of a Parkinson family with a novel PINK1 mutation

Homozygous mutations in the PINK1 gene have been shown to cause early-onset parkinsonism. Here, we describe a novel homozygous mutation (Q126P), identified in two affected German sisters with a clinical phenotype typical for PINK1-associated parkinsonism.We analysed lactate, pyruvate, carnitine and acylcarnitine blood levels, lactate levels under exercise and in the cerebrospinal fluid, activity of respiratory chain complexes I-IV in muscle biopsies and proteasomal activity in immortalized lymphoblasts, but found no evidence for mitochondrial or proteasomal dysfunction. MR spectroscopy revealed raised myoinositol levels in the basal ganglia of both patients, reflecting possible astroglial proliferation.     

Clinical and electrophysiological study in a patient surviving from locked-in syndrome

The results of clinical and electrophysiological investigations in a patient with a locked-in syndrome due to a pontine infarction, mainly on the right side, are presented. EEG showed only slight disturbances, while BAER and SSER revealed response alterations as could be expected from physical examination. BAER revealed altered central conduction after stimulation of either side. After median nerve stimulation on the right side SSER was slightly delayed, while no reproducible cortical response was seen after stimulation on the left side. Our patient survived and showed partial recovery.