Genotype‐phenotype correlations,dystonia and disease progression in spinocerebellar ataxia type 14

Background: Spinocerebellar ataxia type 14 is a rare form of autosomal dominant cerebellar ataxia caused by mutations in protein kinase Cγ gene. Clinically, it presents with a slowly progressive, mainly pure cerebellar ataxia. Methods: Using next generation sequencing, we screened 194 families with autosomal dominant cerebellar ataxia and normal polyglutamine repeats. In‐depth phenotyping was performed using validated clinical rating scales neuroimaging and electrophysiological investigations. Results: We identified 25 individuals from 13 families carrying pathogenic mutations in protein kinase Cγ gene. A total of 10 unique protein kinase Cγ gene mutations have been confirmed of which 5 are novel and 5 were previously described. Our data suggest that the age at onset is highly variable; disease course is slowly progressive and rarely associated with severe disability. However, one third of patients presented with a complex ataxia comprising severe focal and/or task‐induced dystonia, peripheral neuropathy, parkinsonism, myoclonus, and pyramidal syndrome. The most complex phenotype is related to a missense mutation in the catalytic domain in exon 11. Conclusion: We present one of the largest genetically confirmed spinocerebellar ataxia type 14 cohorts contributing novel variants and clinical characterisation. We show that although protein kinase Cγ gene mutations present mainly as slowly progressive pure ataxia, more than a third of cases had a complex phenotype. Overall, our case series extends the phenotype and suggests that protein kinase Cγ gene mutations should be considered in patients with slowly progressive autosomal dominant cerebellar ataxia, particularly when myoclonus, dystonia, or mild cognitive impairment are present in the absence of polyglutamine expansion. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Progressive myoclonic ataxia (the Ramsay Hunt syndrome)

It has been suggested from studies of patients with progressive myoclonus epilepsy that the term Ramsay Hunt syndrome should be abandoned, as its use has led to nosologic confusion, and because, in the light of modern diagnostic techniques, the majority of cases can be allocated to specific disease categories, chiefly, Unverricht-Lundborg disease (Baltic myoclonus) and mitochondrial encephalomyopathy. Review of 30 cases of this syndrome, defined as progressive ataxia and myoclonus and infrequent seizures in the absence of dementia, showed that a clinical or biochemically supported diagnosis could not be made in 43%. This low diagnostic yield probably reflects differences in ascertainment of patients; those described here were referred with a syndrome of progressive myoclonic ataxia (the Ramsay Hunt syndrome) rather than progressive myoclonus epilepsy. These two syndromes share common causes, but a smaller proportion of patients with progressive myoclonic ataxia can currently be diagnosed precisely during life.     

DRPLA: An unusual disease or an underestimated cause of ataxia in Brazil?

BackgroundDentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant spinocerebellar ataxia caused by pathological expansion of CAG trinucleotide repeats in the ATN1 gene. Most cases were described in patients from Japanese ancestry who presented with adult-onset progressive cerebellar ataxia associated with cognitive impairment, choreoathetosis and other movement disorders. DRPLA has been rarely described in Brazilian patients.MethodsWe performed a retrospective observational multicentric study including six different Neurology Centers in Brazil. All patients with genetically confirmed diagnosis of DRPLA had their medical records evaluated and clinical, genetic and neuroimaging features were analyzed.ResultsWe describe of eight Brazilian patients (5 male, 3 female) from four nuclear families with genetically confirmed DRPLA. The most common neurological features included cerebellar ataxia (n = 7), dementia (n = 3), chorea (n = 2), psychiatric disturbances (n = 2), progressive myoclonic epilepsy (n = 2) and severe bulbar signs (n = 1). Progressive myoclonic epilepsy was observed in two juvenile-onset cases before 20-year. A large CAG trinucleotide length was observed in the two juvenile-onset cases and genetic anticipation was observed in all cases. Neuroimaging studies disclosed cerebellar atrophy (n = 6), as well as brainstem and cerebellar atrophy (n = 2) and leukoencephalopathy (n = 1).ConclusionThe patients described herein reinforce that clinical features of DRPLA are highly influenced by age of onset, genetic anticipation and CAG repetition lengths. There is a large complex spectrum of neurological features associated with DRPLA, varying from pure cerebellar ataxia to dementia associated with other movement disorders (myoclonus, choreoathetosis). DRPLA is an unusual cause of cerebellar ataxia and neurodegeneration in Brazilian patients.     

Clinical picture of EPM1-Unverricht-Lundborg disease

Unverricht-Lundborg disease (ULD), progressive myoclonic epilepsy type 1 (EPM1, OMIM254800), is an autosomal recessively inherited neurodegenerative disorder characterized by age of onset from 6 to 16 years, stimulus-sensitive myoclonus, and tonic-clonic epileptic seizures. Some years after the onset ataxia, incoordination, intentional tremor, and dysarthria develop. Individuals with EPM1 are mentally alert but show emotional lability, depression, and mild decline in intellectual performance over time. The diagnosis of EPM1 can be confirmed by identifying disease-causing mutations in a cysteine protease inhibitor cystatin B (CSTB) gene. Symptomatic pharmacologic and rehabilitative management, including psychosocial support, are the mainstay of EPM1 patients' care. Valproic acid, the first drug of choice, diminishes myoclonus and the frequency of generalized seizures. Clonazepam and high-dose piracetam are used to treat myoclonus, whereas levetiracetam seems to be effective for both myoclonus and generalized seizures. There are a number of agents that aggravate clinical course of EPM1 such as phenytoin aggravating the associated neurologic symptoms or even accelerating cerebellar degeneration. Sodium channel blockers (carbamazepine, oxcarbazepine) and GABAergic drugs (tiagabine, vigabatrin) as well as gabapentin and pregabalin may aggravate myoclonus and myoclonic seizures. EPM1 patients need lifelong clinical follow-up, including evaluation of the drug-treatment and comprehensive rehabilitation.     

Myoclonic Alcoholic Epilepsy

We describe 2 patients with chronic alcoholism who over a period of several years developed epilepsy associated with a cerebellar syndrome and action myoclonus. The clinical picture suggested progressive myoclonic epilepsy, but subsequent investigations did not confirm this diagnosis. Myoclonus worsened during abstinence and was relieved during indulgence. We believe that this special clinical syndrome should be recognized as a complication of chronic alcoholism.     

Progressive myoclonic ataxia without ragged red fibres: Unverricht-Lundborg disease vs Ramsay Hunt syndrome

We describe eight patients from three families presenting with myoclonus, ataxia, infrequent seizures and minimal intellectual impairment. All were Arabs from different parts of the Arabian peninsula. The new consensus on terminology, genetic and clinical definition of Baltic myoclonus, Ramsay Hunt syndrome and Unverricht-Lundborg disease suggests that our group are best categorised under the term of progressive myoclonic ataxia of the Unverricht-Lundborg type. Moreover, this report reinforces the existence of this syndrome outside Scandinavia.     

Clinical and Neurophysiological Development of Unverricht-Lundborg Disease in Four Swedish Siblings

Four siblings aged 12-18 years with progressive myoclonus epilepsy demonstrated a subclinical stage at the age of 9-11 years, with visual blackouts and polyspike electroencephalographic (EEG) activity on photic stimulation, an early myoclonic stage at the age of 12-15 years, with increasing segmental, stimulus-sensitive myoclonus, occasional nocturnal buildup myoclonic "cascade" seizures, slowing of EEG alpha-activity, episodic 4-6 Hz bilateral sharp waves and polyspikes with myoclonias on photic stimulation, and a disabling myoclonic stage at the age of 16-18 years, with periodic generalized myoclonias, nocturnal myoclonic "cascade" seizures, ataxia, dysarthria, mental changes, intermittent wheelchair dependency, and continuous EEG slow waves with polyspikes and intense myoclonias on photic stimulation. One of the siblings died at the age of 18 years with no apparent cause of death. Treatment with antiepileptic drugs other than valproate may have contributed but none of the siblings were ever treated with phenytoin. Extensive clinical and laboratory investigations revealed no abnormalities and excluded other known possible causes of progressive myoclonus epilepsy. The diagnosis was consistent with Unverricht-Lundborg disease and rested on typical age of onset, clinical signs, EEG, and evoked response abnormalities. Buildup myoclonic seizures are typical in advanced stages of Unverricht-Lundborg disease. We have labeled these myoclonic "cascade" seizures. A typical seizure was studied with video-EEG and cardiorespiratory monitoring. Characteristics revealed were onset with continuous arrhythmic myoclonic jerks followed by intense rhythmic myoclonus with increasing muscle tone that successively reduced the amplitude of the jerks. The EEG during the whole seizure showed intense polyspike activity. Obstructive apnea was seen at the peak of the seizure. There were no cardiac dysrhythmias. Consciousness was normal or only slightly impaired. Postictal drowsiness was not observed. Myoclonic "cascade" seizures are easily confused with generalized tonic-clonic seizures.     

Progressive myoclonus epilepsy: dentato-rubro-pallido-luysian atrophy (DRPLA) in childhood

A 22-year-old female with progressive myoclonus epilepsy (PME) considered to be due to hereditary dentato-rubro-pallido-luysian atrophy (DRPLA) was reported. Some of her family members showed progressive myoclonus, seizures, dementia, ataxia and choreoathetosis, with variation of onset from childhood to adult life, which suggested that they had been suffering from DRPLA. CT scan and MRI studies, including some on family members, revealed cerebral and cerebellar atrophy accompanied by dilatation of the fourth ventricle, compatible with the findings in DRPLA reported previously. We emphasize that a detailed family history may be essential in dealing with a PME patient and that DRPLA should be considered in the differential diagnosis of the PME syndrome with onset in childhood, in Japan.     

Progressive myoclonus ataxia: Time for a new definition?

Background: The clinical demarcation of the syndrome progressive myoclonus ataxia is unclear, leading to a lack of recognition and difficult differentiation from other neurological syndromes. Objectives: The objective of this study was to apply a refined definition of progressive myoclonus ataxia and describe the clinical characteristics in patients with progressive myoclonus ataxia and with isolated cortical myoclonus. Methods: A retro‐ and prospective analysis was performed in our tertiary referral center between 1994 and 2014. Inclusion criteria for progressive myoclonus ataxia patients were the presence of myoclonus and ataxia with or without infrequent (all types, treatment responsive) epileptic seizures. Inclusion criteria for isolated cortical myoclonus was the presence of isolated cortical myoclonus. Clinical and electrophysiological characteristics data were systematically scored. Results: A total of 14 progressive myoclonus ataxia patients (males, 7; females, 7), median age 14.5 years, and 8 isolated cortical myoclonus patients (males, 2; females, 6), median age 23.5 years, were identified. In 93% of the progressive myoclonus ataxia patients, ataxia started first (median 2 years) followed by myoclonus (4 years) and finally infrequent epilepsy (9.3 years), with a progressive course in 93%. In 64% of the progressive myoclonus ataxia patients, a genetic underlying etiology was identified, including 3 not earlier reported causative progressive myoclonus ataxia genes. In isolated cortical myoclonus patients, myoclonus started at (median) 12 years with progression over time in 63% and a single epileptic seizure in 1 patient. No genetic causes were identified. Conclusion: Using a refined definition, we could create a rather homogenous progressive myoclonus ataxia group. Patients with isolated cortical myoclonus have a different course and do not appear to evolve in progressive myoclonus ataxia. The refined progressive myoclonus ataxia definition is a successful first step toward creating a separate syndrome for both clinical practice and future genetic research. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Pattern-sensitive epilepsy: electroclinical characteristics, natural history, and delineation of the epileptic syndrome

PURPOSE: To elucidate the electroclinical features and long-term outcome of patients with pattern-sensitive epilepsy. METHODS: We reviewed the clinical and electroencephalographic (EEG) findings of 73 (43 female and 30 male) patients in whom pattern-sensitive epilepsy was diagnosed at Mayo Clinic (Rochester, Minnesota, U.S.A.) from 1950 through 1999. We contacted patients and their relatives by letter or telephone to obtain the latest seizure and quality-of-life outcomes. RESULTS: The median age at onset of seizures was 12.8 years (range, 0.6-32.9 years). Most patients had absence, myoclonic, or generalized tonic-clonic seizures. Interictal epileptiform discharges in the EEG were detected in 61 (83.6%) patients and were generalized in 54 (74%). Paroxysmal epileptiform discharges in the EEG elicited with standard patterns were all generalized in two thirds of patients but were restricted to the posterior head region in one-third. Eight (11%) patients did not exhibit photosensitivity. Television was the most common precipitant [30 patients (41%)]. Twenty-nine patients gave a clear history of one or more seizures precipitated while viewing environmental patterns such as window screens, garments, tablecloths, and ceiling tiles; the rest of the patients admitted that they preferred to avoid looking at patterned objects because these objects made them uncomfortable. The electroclinical features suggested juvenile myoclonic epilepsy in 14 patients, progressive myoclonus epilepsy in three, progressive familial cerebellar ataxia with myoclonus in two, and severe myoclonic epilepsy of infancy in one. During a median follow-up period of 15.7 years, 25 (45.5%) of 55 patients who were followed up for > or =5 years achieved complete seizure remission. The median age at remission was 24.4 years. The absence of progressive neurologic disease was correlated significantly with remission; a family history of seizures showed a trend in favor of remission. More than two thirds of the patients did not consider the seizures an impediment to their family life or to educational and occupational achievements. CONCLUSIONS: Although pattern sensitivity as a trait occurs in various epileptic syndromes, pattern-sensitive epilepsy is a readily distinguishable subtype of the visually provoked reflex epilepsies. In our opinion, the location and extent of the excitable region or regions within the visual cortex concerned with different attributes of visual function dictate susceptibility to a specific trigger (intermittent light, pattern, or color) or closely related multiple triggers and the resultant electroclinical phenomenon.     

Juvenile neuroaxonal dystrophy: clinical, electrophysiological, and neuropathological features.

We describe 2 brothers with progressive myoclonus epilepsy that began in the second decade and was associated with cerebellar ataxia and intellectual deterioration. Electroencephalographic and cerebral evoked potential studies showed findings associated with myoclonus epilepsy. Neuropathological examination of 1 of the brothers, who died at age 23 years, revealed widespread changes of neuroaxonal dystrophy without pigment deposition in the basal ganglia. We propose the term juvenile neuroaxonal dystrophy (JNAD) to distinguish this condition on clinical grounds from infantile neuroaxonal dystrophy on the one hand, and on clinical and pathological grounds from Hallervorden-Spatz disease on the other hand. JNAD, while exceedinly rare, must be considered in the differential diagnosis of the progressive myoclonus epilepsies.     

青少年肌阵挛性癫(癎)

青少年肌阵挛性癫是一种以晨起肌阵挛、全身强直-阵挛发作为临床特征的特发性全身性癫综合征,有时伴有失神发作。本文就青少年肌阵挛性癫的临床表现、遗传学、脑电图特点、鉴别诊断以及治疗方法进行了阐述。     

Myoclonus in mitochondrial disorders

Myoclonus is a possible manifestation of mitochondrial disorders, and its presence is considered, in association with epilepsy and the ragged red fibers, pivotal for the syndromic diagnosis of MERRF (myoclonic epilepsy with ragged red fibers). However, its prevalence in mitochondrial diseases is not known. The aims of this study are the evaluation of the prevalence of myoclonus in a big cohort of mitochondrial patients and the clinical characterization of these subjects. Based on the database of the “Nation‐wide Italian Collaborative Network of Mitochondrial Diseases,” we reviewed the clinical and molecular data of mitochondrial patients with myoclonus among their clinical features. Myoclonus is a rather uncommon clinical feature of mitochondrial diseases (3.6% of 1,086 patients registered in our database). It is not strictly linked to a specific genotype or phenotype, and only 1 of 3 patients with MERRF harbors the 8344A>G mutation (frequently labeled as “the MERRF mutation”). Finally, myoclonus is not inextricably linked to epilepsy in MERRF patients, but more to cerebellar ataxia. In a myoclonic patient, evidences of mitochondrial dysfunction must be investigated, even though myoclonus is not a common sign of mitochondriopathy. Clinical, histological, and biochemical data may predict the finding of a mitochondrial or nuclear DNA mutation. Finally, this study reinforces the notion that myoclonus is not inextricably linked to epilepsy in MERRF patients, and therefore the term “myoclonic epilepsy” seems inadequate and potentially misleading. © 2014 International Parkinson and Movement Disorder Society     

NARP syndrome and adult-onset generalised seizures.

The neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) syndrome is a maternally inherited disorder attributable to a heteroplasmic mtDNA point mutation. Catastrophic epilepsy may accompany severe, early onset forms of NARP, but seizures seem to be rare in cases with adolescent and adult onset. We describe a patient who developed clumsiness and visual problems in her teens. She had no clinical seizures but an EEG showed generalized spike and wave discharges. At this time the patient remained without a specific diagnosis. At the age of 21, the patient developed progressive ataxia and she also experienced a tonic-clonic status epilepticus. Further examinations revealed NARP syndrome. EEG abnormalities may precede adult onset seizures in the NARP syndrome.     

Rapidly progressive phenotype of Lafora disease associated with a novel NHLRC1 mutation

Lafora disease is a fatal, autosomal recessive form of progressive myoclonus epilepsy. Patients characteristically exhibit myoclonic and tonic-clonic seizures and cognitive impairment, beginning in their second decade. Alterations in two genes were identified as the cause of the disease. Mutations in the NHL repeat containing 1 (NHLRC1) gene were described in association with a more benign clinical course and later age of death, compared with epilepsy progressive myoclonus type 2A (EPM2A) mutations. We describe a rapidly progressive phenotype of Lafora disease in an adolescent patient with a novel NHLRC1 mutation. He developed severe disability and dementia less than 2 years after the onset of signs.     

Myoclonic epilepsy masquerading as a tic disorder

Myoclonic epilepsies comprise a heterogeneous group of epileptic syndromes characterized by myoclonic jerks, generalized tonic-clonic seizures (GTCSs), and sometimes absence seizures (multiplicity of seizure types). JME (Juvenile Myoclonic Epilepsy) is relatively common and usually responds well to treatment with appropriate anticonvulsants. Others like the progressive myoclonic epilepsy syndromes are relentlessly progressive, associated with cognitive decline and respond poorly to anticonvulsants. Myoclonic epilepsy is frequently misdiagnosed until the patient is specifically asked about the leading symptom, i.e., jerky movements occurring in the morning. We present here a patient who had been misdiagnosed as a tic disorder and treated for the past many years before the correct diagnosis of myoclonic epilepsy was made during an admission for Video-EEG monitoring.     

Early-onset progressive encephalophathy with migrant,continuous myoclonus

Three unusual cases of focal continuous myoclonus with onset during the first months of life, lasting from dozens of minutes to hours, are reported. During disease evolution, prolonged bilateral myoclonic seizures and generalized tonic-clonic seizures occur. Subsequently, a progressive encephalopathy with hypotonia and ataxia appears. A net worsening of the neurological condition is observed after the age of 4–5 years. Cortical atrophy is shown by CCT and MRI. Neurometabolic screening is not contributory. Repeated polygraphic recordings show continuous and segmental myoclonic jerks, localized in different muscles, at frequencies ranging between 0.5–1 c/s and 6–8 c/s. Moreover action myoclonus is recorded. During the first period of disease the EEG does not show any paroxysmal activity. As to the classification, this syndrome corresponds to an early onset progressive encephalopathy of unknown origin, similar in some aspects to Alper's disease. Another problem is the interpretation of the myoclonic phenomena. Some important aspects suggest a cortical origin of the diverse myoclonic phenomena observed in these cases.