Ramsay Hunt syndrome: New impressions in the era of molecular genetics.

More frequent use of next-generation sequencing led to a paradigm shift in assessing heredodegenerative diseases. This is particularly notable in progressive myoclonus epilepsy (PME) and progressive myoclonus ataxia (PMA) where a group of disorders linked to novel genetic mutations has now been added to these phenotypical realms. Despite the historical value of Ramsay Hunt's contribution defining the syndrome later known as PMA, recent genetic developments have made this eponym obsolete and a new definition and classification of PMA and PME seem necessary. A rational possibility is to adopt the wider term progressive myoclonus ataxia and epilepsy syndrome (PMAES), which can be subdivided into its main subtypes, PME and PMA, whenever clinical data is sufficient to make that distinction.

Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder.

GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons. Furthermore, knock down of rigor mortis, the fly homolog of human GEMIN5, leads to developmental defects, motor dysfunction, and a reduced lifespan. Interestingly, we observed that GEMIN5 variants disrupt a distinct set of transcripts and pathways as compared to SMA patient neurons, suggesting different molecular pathomechanisms. These findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome.

Ramsay Hunt syndrome: clinical characterization of progressive myoclonus ataxia caused by GOSR2 mutation.

BACKGROUND: Ramsay Hunt syndrome (progressive myoclonus ataxia) is a descriptive diagnosis characterized by myoclonus, ataxia, and infrequent seizures. Often the etiology cannot be determined. Recently, a mutation in the GOSR2 gene (c.430G>T, p.Gly144Trp) was reported in 6 patients with childhood-onset progressive ataxia and myoclonus. METHODS: We evaluated 5 patients with cortical myoclonus, ataxia, and areflexia. RESULTS: All 5 patients had the same homozygous mutation in GOSR2. Here we present their clinical and neurophysiological data. Our patients (aged 7-26 years) all originated from the northern Netherlands and showed a remarkably homogeneous phenotype. Myoclonus and ataxia were relentlessly progressive over the years. Electromyography revealed signs of sensory neuronopathy or anterior horn cell involvement, or both, in all patients with absent reflexes. CONCLUSIONS: Based on the presented phenotype, we would advise movement disorder specialists to consider mutation analysis of GOSR2 in patients with Ramsay Hunt syndrome, especially when they also have areflexia.

Exome sequencing reveals a novel MRE11 mutation in a patient with progressive myoclonic ataxia.

Progressive myoclonic ataxia (PMA) is a clinical syndrome defined as progressive ataxia and myoclonus and infrequent seizures in the absence of progressive dementia. Due to the extremely heterogeneous nature of PMA, a large proportion of PMA cases remain molecularly undiagnosed. The aim of this study was to clarify the molecular etiology of PMA. The patient was a 52-year-old female from consanguineous parents. She developed a jerking neck movement at age 9, which gradually expanded to her entire body. On physical examination at age 47, she exhibited generalized, spontaneous myoclonus that occurred continuously. She also presented with mild limb and truncal ataxia. An electroencephalogram revealed no abnormalities. A brain MRI displayed no atrophy of the cerebellum. Electrophysiological studies suggested myoclonus of a subcortical origin. For further evaluation, we performed exome sequencing, and we identified a novel homozygous missense mutation in the MRE11 gene (NM_005590:c.140C>T:p.A47V). Subsequently, we analyzed the expression of MRE11 and related proteins (RAD50 and NBS1) via Western blot, and they were markedly decreased compared to a healthy control. Mutations in the MRE11 gene have been known to cause an ataxia-telangiectasia-like (ATLD) disorder. Accumulating evidence has indicated that its wide phenotypic variations in ATLD correspond to genotypic differences. Interestingly, our case exhibited a relatively mild decrease in NBS1 compared to previously reported cases of a homozygous missense mutation, which may account for the milder phenotype in this patient. Moreover, together with a recently reported case of an MRE11 mutation, it is suggested that MRE11 mutations can present as PMA.

Clinical, genetic, and therapeutic diversity in 2 patients with severe mevalonate kinase deficiency.

Mevalonic aciduria (MA) represents the severest form of mevalonate kinase deficiency due to recessively inherited, loss-of-function MVK mutations. MA is an early-onset disorder characterized by a marked failure to thrive, diverse neurologic symptoms, dysmorphic features, and recurrent febrile episodes. However, significant clinical differences have been reported in the few cases published to date. Here we describe 2 unrelated Spanish patients with MA, emphasizing the clinical heterogeneity observed. One patient presented with the severe classic MA phenotype due to the homozygous p.Ile-268-Thr MVK genotype, with a poor response to conventional treatments. However, the anti-interleukin 1 agent anakinra in this patient resulted in improvement in many clinical and laboratory parameters. The second patient presented with an atypical milder phenotype because of an older age at disease onset, mild neurologic symptoms, absence of febrile episodes and dysmorphic features, and moderate-to-good response to conventional treatments. The novel p.Arg-241-Cys MVK mutation, associated with the already known p.Ser-135-Leu mutation, detected in this patient expands the genetic diversity of mevalonate kinase deficiency. This atypical presentation of MA suggests that it should be included in the differential diagnosis of unclassified patients with psychomotor retardation, failure to thrive or ataxia, even in the absence of febrile episodes.

Early-onset cerebellar atrophy associated with mutation in the CACNA1A gene.

Mutations in the CACNA1A gene were described in familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6. Familial hemiplegic migraine and episodic ataxia type 2 are caused by point mutations in the CACNA1A gene, and spinocerebellar ataxia type 6 develops as a result of a CAG triple expansion in exon 1 of the gene. Phenotypic variability and clinical overlap are well recognized. We describe a 3-year-old child with clinical and radiologic signs of early-onset cerebellar atrophy. The family history was significant for migraine, and in some members of the family, a diagnosis of hemiplegic migraine was established. The combination of cerebellar atrophy in our patient and the family history suggested involvement of the CACNA1A gene. The sequence analysis of genomic DNA from the proband identified heterozygosity for a mutation (Thr666Met) in the CACNA1A gene. Subsequently, his father, who was mildly affected, and two other relatives were demonstrated to carry the same mutation. Therefore, CACNA1A gene mutations should be considered in the differential diagnosis of congenital cerebellar atrophy.

Searching for mutation in the JPH3, ATN1 and TBP genes in Polish patients suspected of Huntington's disease and without mutation in the IT15 gene.

BACKGROUND AND PURPOSE: The aim of this study was to perform DNA analysis in patients with clinical diagnosis of Huntington's disease (HD) after molecular exclusion of HD and further molecular examinations for other neurodegenerative diseases such as Huntington's disease-like 2 (HDL-2; gene JPH3), dentatorubral pallidoluysian atrophy (DRPLA; gene ATN1) and spinocerebellar ataxia type 17 (SCA17; gene TBP). MATERIAL AND METHODS: The material comprised 224 DNA samples isolated from peripheral blood from patients suspected of HD and 100 DNA samples from unaffected controls. The control group was used to determine the normal range of the number of CAG/CTG repeats in genes JPH3, ATN1 and TBP in the Polish population. Molecular analysis was carried out by PCR reaction, embracing microsatellite repeats in genes JPH3, ATN1 and TBP with specific, fluorescently labelled primers. PCR products were separated in polyacrylamide gels. The normal ranges of the number of repeats established for the control group in genes JPH3, ATN1 and TBP were 7-19, 9-27 and 29-45, respectively. RESULTS: Molecular analysis of DNA from 224 individuals suspected of HD (117 women and 107 men) revealed one case of dynamic mutation - 55 CAG repeats - in the TBP locus (SCA17). No cases of DRPLA or HDL-2 were detected. The range of CAG/CTG repeats for the JPH3 gene in the patient group was 11-19, with the most common alleles containing 14 and 16 repeats. For the ATN1 gene in patients the range of 8-27 repeats was established and the most frequent allele with 16 triplets was present. CONCLUSIONS: The study on 244 patients referred with the clinical diagnosis of HD and without mutation of the IT15 gene revealed one case of SCA17 but did not disclose the presence of two other diseases with a similar clinical manifestation: DRPLA and HDL2.

Diffuse multicystic encephalomalacia in a preterm baby due to homozygous methylenetetrahydrofolate reductase 677 C-->T mutation.

Methylenetetrahydrofolate reductase catalyzes the formation of 5-methyltetrahydrofolate from 5,10-methylentetrahydrofolate and produces folate for the methylation of homocysteine to methionine. Due to insufficient conversion of homocysteine to methionine, plasma homocysteine levels increase in methylenetetrahydrofolate reductase deficiency. Homocysteine is an amino acid that contains a neurotoxic sulfur molecule and can induce neuronal apoptosis. Methylenetetrahydrofolate reductase deficiency is 1 of the etiological factors that causes neurological symptoms and signs in the newborn and childhood period. Here, we report a premature baby with prenatal onset diffuse multicystic encephalomalacia and cerebellar atrophy due to homozygous methylenetetrahydrofolate reductase mutation.

Relative frequencies of CAG expansions in spinocerebellar ataxia and dentatorubropallidoluysian atrophy in 116 Italian families.

Two hundred and forty-eight patients from 116 Italian families with dominant ataxia were studied for CAG expansion within SCA1, 2, 3, 6, 7 (spinocerebellar ataxia) and DRPLA (dentatorubropallidoluysian atrophy) genes. Fifty-six percent of the families originated from Southern, 19% from Central and 25% from Northern Italy. SCA2 was the commonest mutation, accounting for 47% of the families, followed by SCA1 (24%), SCA6 (2%), SCA7 (2%) and DRPLA (1%). No SCA3 family was found. Twenty-four percent of the families carried a still unidentified mutation. When occurrence of mutations was evaluated according to the geographic origin, SCA1 was the commonest in Northern (72%), whereas SCA2 was prevalent (63%) in Southern Italy. The number of CAG repeats in SCA1 normal alleles was higher in Northern than in Central-Southern Italy.

Homozygosity mapping of spinocerebellar ataxia with cerebellar atrophy and peripheral neuropathy to 9q33-34, and with hearing impairment and optic atrophy to 6p21-23.

With the availability of a simple molecular test that distinguishes Friedreich ataxia, the most frequent form of inherited ataxia, from other recessive ataxias, it now becomes possible to unravel the genetic heterogeneity of the latter. We have now localised two genes causing autosomal recessive spinocerebellar ataxia in two consanguineous families. In the first family, the four affected Japanese sibs had spinocerebellar ataxia associated with elevated levels of serum creatine kinase, gamma-globulin, and alpha-foetoprotein. Homozygosity over a 20 cM region allowed to demonstrate linkage at 9q33.3-34.3 with a lod score of 3.0. Genotyping two unrelated Japanese patients from first degree consanguineous parents revealed that one was homozygous for the same region but did not share the biochemical features. In the second family, an Israeli uncle and a niece were affected by an early-onset recessive ataxia and subsequently developed hearing impairment and optic atrophy. Homozygosity over a 17 cM region allowed demonstration of linkage at 6p21-23 with a lod score of 3.25. These two localisations of autosomal recessive ataxia genes represent a first step toward the identification of genetically homogenous, non-Friedreich, ataxic patients and subsequent cloning of the genes.

Abnormal gene product identified in hereditary dentatorubral-pallidoluysian atrophy (DRPLA) brain.

Dentatorubral-pallidoluysian atrophy (DRPLA) is associated with the expansion of an unstable CAG repeat. Using antibodies against a synthetic peptide corresponding to the sequence of the DRPLA gene product C terminus, we have identified the DRPLA gene product in normal human brains as a approximately 190 kD protein. We also find a larger approximately 205 kD protein specifically in DRPLA brains. Immunohistochemically, the DRPLA gene product is observed mainly in the neuronal cytoplasm. Our results demonstrate the existence of the expanded CAG repeat gene product and support the possibility that the expanded CAG-encoded polyglutamine stretch may participate in the pathological process of the similar trinucleotide repeat diseases.

DNA analysis in hereditary dentatorubral-pallidoluysian atrophy: correlation between CAG repeat length and phenotypic variation and the molecular basis of anticipation.

Hereditary dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disease with variable clinical phenotypes. Progressive ataxia, choreoathetosis, and dementia are the main clinical features of adult-onset cases, whereas the main feature in juvenile-onset DRPLA is progressive myoclonus epilepsy. Earlier onset is apparent in successive generations (anticipation). The molecular abnormality underlying DRPLA is an expanded, unstable CAG trinucleotide repeat on chromosome 12p. We analyzed 71 DNA samples obtained from 12 Japanese DRPLA pedigrees that included 38 affected individuals. Normal alleles had 7 to 23 repeats, DRPLA alleles 53 to 88 repeats. DRPLA alleles also were detected in five asymptomatic family members. Patients with juvenile onset had significantly larger repeats than did those with adult onset, and there was a significant negative correlation between CAG repeat length and age at onset. In 80% of the paternal transmissions, there was an increase of more than five repeats, whereas all the maternal transmissions showed either a decrease or an increase of fewer than five repeats. There was a significant correlation between father-child differences in repeat length and differences in age at onset. The analysis of CAG repeat length is a reliable diagnostic test for DRPLA and is of value for the presymptomatic detection of individuals at risk. The expansion of CAG repeats is important in phenotypic variation and anticipation. In addition, the sex of the transmitting parent has a significant effect on the molecular mechanism of anticipation.

Oculomotor abnormalities in Dyssynergia cerebellaris myoclonica.

In 1921 Ramsay-Hunt first described the syndrome of dyssynergia cerebellaris myoclonica (DCM), characterized by the clinical triad of action myoclonus, progressive ataxia and epilepsy with cognitive impairment, subsequently also referred to as the "Ramsay-Hunt syndrome". The cause of the symptoms of this rare degenerative syndrome (incidence: 500,000) is the impairment of a regulatory mechanism between nucleus dentatus, nucleus ruber and the bulbar olive. We present two sisters, aged 29 and 30 years, who were investigated for oculomotor abnormalities. The patients were diagnosed as having DCM according to clinical symptomatology, which was confirmed by neurophysiological and radiological findings. In both cases saccadic velocity was markedly reduced, whereas saccadic latency showed a significant increase. In addition, smooth pursuit eye-movements were abnormal and presented reduced gain. These findings suggest that pontine areas and the vestibulocerebellum also seem to be affected in DCM.

Ramsay Hunt syndrome: progressive mental deterioration in association with unusual cerebral white matter change.

An autopsied case of Ramsay Hunt syndrome with progressive dementia was reported. The clinical symptoms included progressive intellectual decline, myoclonus, generalized convulsive seizure, cerebellar ataxia and positive pyramidal signs. Neuropathological examination disclosed cerebral white matter demyelination marked in the frontal lobe and fibrillary gliosis predominantly in the subcortical U-fibers, grumose degeneration in the dentate nucleus and inferior olivary nucleus lesion. The skeletal muscle showed no ragged-red fiber. The present case can be included in Ramsay Hunt syndrome because of the absence of pathological hallmark of mitochondrial encephalomyopathy and of the presence of the degenerative lesions in the olivary and dentate nucleus without cerebellar Purkinje cell loss. The intellectual decline is a result of extensive frontal white matter change, and myoclonus and ataxia are closely associated with dentate grumose degeneration. The cerebral white matter change is an unusual finding and the present case might be a variant in Ramsay Hunt syndrome.

Progressive myoclonus epilepsies: an electroclinical, biochemical, morphological and molecular genetic study of 17 cases.

Electroclinical, morphological, biochemical and molecular genetic data from 17 patients affected by progressive myoclonus epilepsies (PME) are reported. Twelve patients were characterized by prominent action myoclonus, sporadic seizures, mild ataxia, lack of dementia and persistence of normal EEG background activity; three patients showed a more rapid worsening of symptomatology, characterized by early mental impairment, massive and action myoclonus, cerebellar signs and tonic clonic seizures; in these patients EEG background activity was slow, even in early stages of the disease. In two patients, previously classified as cryptogenetic PME, a mitochondrial aetiology was recognized by the presence of ragged red fibers in muscle biopsy and by a reduction of the respiratory chains enzymes. Molecular genetical investigation of mtDNA demonstrated the reported heteroplasmic point mutation at nt 8344 of mtDNA in the two MERRF patients, while it was negative in all of the others.