Involuntary moaning in a Hispanic family with eight affected members.

Involuntary moaning has been reported in sporadic cases of neurodegenerative diseases. A five-generation Hispanic family with eight members exhibiting involuntary moaning, most of whom with isolated moaning in the absence of any additional neurological disorder carried a missense variant in the NEFH gene segregating in the family.

Charcot-Marie-Tooth Disease and Other Hereditary Neuropathies.

PURPOSE OF REVIEW: This article provides an overview of Charcot-Marie-Tooth disease (CMT) and other inherited neuropathies. These disorders encompass a broad spectrum with variable motor, sensory, autonomic, and other organ system involvement. Considerable overlap exists, both phenotypically and genetically, among these separate categories, all eventually exhibiting axonal injury and neurologic impairment. Depending on the specific neural and non-neural localizations, patients experience varying morbidity and mortality. Neurologic evaluations, including neurophysiologic testing, can help diagnose and predict patient disabilities. Diagnosis is often complex, especially when genetic and acquired components overlap. RECENT FINDINGS: Next-generation sequencing has greatly improved genetic diagnosis, with many third-party reimbursement parties now embracing phenotype-based panel evaluations. Through the advent of comprehensive gene panels, symptoms previously labeled as idiopathic or atypical now have a better chance to receive a specific diagnosis. A definitive molecular diagnosis affords patients improved care and counsel. The new classification scheme for inherited neuropathies emphasizes the causal gene names. A specific genetic diagnosis is important as considerable advances are being made in gene-specific therapeutics. Emerging therapeutic approaches include small molecule chaperones, antisense oligonucleotides, RNA interference, and viral gene delivery therapies. New therapies for hereditary transthyretin amyloidosis and Fabry disease are discussed. SUMMARY: Comprehensive genetic testing through a next-generation sequencing approach is simplifying diagnostic algorithms and affords significantly improved decision-making processes in neuropathy care. Genetic diagnosis is essential for pathogenic understanding and for gene therapy development. Gene-targeted therapies have begun entering the clinic. Currently, for most inherited neuropathy categories, specific symptomatic management and family counseling remain the mainstays of therapy.

The Neuropsychiatry of Huntington Disease-Like 2: A Comparison with Huntington's Disease.

BACKGROUND: Huntington Disease-Like 2 (HDL2) is a rare autosomal dominant disorder caused by an abnormal CAG/CTG triplet repeat expansion on chromosome 16q24. The symptoms of progressive decline in motor, cognitive and psychiatric functioning are similar to those of Huntington's disease (HD). The psychiatric features of the HDL2 have been poorly characterized. OBJECTIVE: To describe the neuropsychiatric features of HDL2 and compare them with those of HD. METHODS: A blinded cross-sectional design was used to compare the behavioural component of the Unified Huntington's Disease Rating Scale (UHDRS) in participants with HDL2 (n = 15) and HD (n = 13) with African ancestry. RESULTS: HDL2 patients presented with psychiatric symptoms involving mood disturbances and behavioural changes that were not significantly different from those in the HD group. Duration of disease and motor performance correlated (p < 0.001) with the Functional Capacity score and the Independence score of the UHDRS. HD patients reported movement dysfunction as the first symptom more frequently than HDL2 Patients (p < 0.001). CONCLUSION: The psychiatric phenotype of HDL2 is similar to that of HD and linked to motor decline and disease duration. Psychiatric symptoms seem more severe for HDL2 patients in the early stages of the disease.

Blended phenotype of AP4E1 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 15.

Atypical phenotype of an imprinting disease can develop with a recessive homozygous variant due to uniparental isodisomy. We present a girl with severe intellectual disability, developmental delay, distinctive facial features, and other neuropsychiatric features. Trio whole exome sequencing revealed a novel homozygous frameshift variant in AP4E1 [NM_007347.5:c.2412dupT:p.(Gly805Trpfs*8)] and uniparental isodisomy of chromosome 15 [iUPD(15)]. Single nucleotide polymorphism mapping analysis of exome data showed that the homozygous AP4E1 variant was derived from her heterozygous carrier father and unmasked by paternal iUPD(15). Brain magnetic resonance imaging confirmed the brain abnormalities characteristic of AP4 deficiency including the dilated ventricles and hypointensity in the globus pallidus in susceptibility-weighted imaging. This is the first case report of a combination of AP4E1 deficiency and Angelman syndrome. Our patient indicates that whole exome sequencing could uncover an atypical phenotype caused by multiple genetic factors including the uniparental isodisomy.

Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration.

Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.

The neuropsychological deficits and dissociations in Huntington Disease-Like 2: A series of case-control studies.

OBJECTIVES: Huntington's Disease Like-2 (HDL2) is a rare autosomal dominant genetic disease caused by a mutation in the JPH3 gene. The Huntington's Disease (HD) phenocopy has the greatest clinical resemblance to HD, but its neurocognitive characterisation is poorly researched. This study reports on the neurocognitive profile of seven HDL2 patients including preserved functions, deficits and dissociations (classical and strong) and provides a general characterisation of the cognitive dysfunction of HDL2 in relation to the progression of the disease. METHODS: The neuropsychological performance of seven HDL2 patients were compared to one of four control groups, matched by age and level of education using a Single Case-Control design. All patients were polyglots and with public education (primary and secondary). Deficits, as well as classical and strong dissociations within each case profile, were identified by implementing Crawford and Howell's (1998) t-test and the Revised Standardized Difference Test (Crawford and Garthwaite, 2005), respectively. RESULTS: The HDL2 neurocognitive syndrome is heterogeneous with a variable rate of progression, with the psychomotor and dexterity domain consistently and severely impaired. CONCLUSION: HDL2 has a heterogeneous impact on cognitive functions from early stages in the disease, which evolve to dementia in a non-uniform manner, in keeping with preferential damage in the cerebrocortical-basal ganglia-thalamus-cerebrocortical circuit.

Disorders of mitochondrial dynamics in peripheral neuropathy: Clues from hereditary neuropathy and diabetes.

Peripheral neuropathy is a common and debilitating complication of diabetes and prediabetes. Recent clinical studies have identified an association between the development of neuropathy and dyslipidemia in prediabetic and diabetic patients. Despite the prevalence of this complication, studies identifying molecular mechanisms that underlie neuropathy progression in prediabetes or diabetes are limited. However, dysfunctional mitochondrial pathways in hereditary neuropathy provide feasible molecular targets for assessing mitochondrial dysfunction in neuropathy associated with prediabetes or diabetes. Recent studies suggest that elevated levels of dietary saturated fatty acids (SFAs) associated with dyslipidemia impair mitochondrial dynamics in sensory neurons by inducing mitochondrial depolarization, compromising mitochondrial bioenergetics, and impairing axonal mitochondrial transport. This causes lower neuronal ATP and apoptosis. Conversely, monounsaturated fatty acids (MUFAs) restore nerve and sensory mitochondrial function. Understanding the mitochondrial pathways that contribute to neuropathy progression in prediabetes and diabetes may provide therapeutic targets for the treatment of this debilitating complication.

MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy.

MPV17 encodes a putative channel-forming protein of the inner mitochondrial membrane and is involved in mitochondrial deoxynucleotide homeostasis. MPV17 mutations were first reported in patients with Navajo neurohepatopathy, an autosomal recessive mitochondrial DNA depletion syndrome, characterized by early-onset liver failure, failure to thrive as well as central and peripheral neurological involvement. Recently, two patients with juvenile-onset peripheral sensorimotor neuropathy associated with an MVP17 c.122G>A (p.Arg41Gln) variant have been reported. Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants. Patients of the first family carried the known c.122G>A variant and affected individuals of the second family had a novel c.376-9T>G near-splice variant, which was shown to result in an in-frame deletion of 11 amino acids. This report provides further evidence that MPV17 mutations should be considered in patients with pure, non-syndromic axonal neuropathy.

Current state of knowledge in Chorea-Acanthocytosis as core Neuroacanthocytosis syndrome.

Neuroacanthocytosis (NA) syndromes are a group of rare diseases characterized by neurological disorders and misshaped spiky red blood cells (acanthocytes) including Chorea-Acanthocytosis (ChAc), McLeod syndrome (MLS), Huntington disease-like 2 (HDL 2), pantothenate kinase-associated neurodegeneration (PKAN), abeta- and hypobetalipoproteinemia and aceruloplasminemia. This clinically and genetically heterogeneous group of diseases shares main clinical features presenting most often as a hyperkinetic movement disorder. Even though these are long noted disease conditions, we still know only little on the underlying disease mechanisms. The current review focuses upon ChAc as the core entity of NA syndromes caused by mutations in the VPS13A gene. The support of patient organizations and the ERA-NET initiative yielded to different multidisciplinary efforts with significant progress on our understanding of ChAc. Disturbances in two pathways are currently considered to be significantly involved in the pathophysiology of ChAc, namely elevated Lyn kinase phosphorylation and decreased signaling via Phosphoinositide 3-kinase (PI3K). These recent developments may reveal potential drugable targets for causative therapies of ChAc.

A Systematic Review of the Huntington Disease-Like 2 Phenotype.

BACKGROUND: Huntington Disease-like 2 (HDL2) is a neurodegenerative disorder similar to Huntington Disease (HD) in its clinical phenotype, genetic characteristics, neuropathology and longitudinal progression. Proposed specific differences include an exclusive African ancestry, lack of eye movement abnormalities, increased Parkinsonism, and acanthocytes in HDL2. OBJECTIVE: The objective was to determine the similarities and differences between HD and HDL2 by establishing the clinical phenotype of HDL2 with the published cases. METHODS: A literature review of all clinically described cases of HDL2 until the end of 2016 was performed and a descriptive analysis was carried out. RESULTS: Sixty-nine new cases were described between 2001 and 2016. All cases had likely African ancestry, and most were found in South Africa and the USA. Many features were found to be similar to HD, including a strong negative correlation between repeat length and age of onset. Chorea was noted in 48/57 cases (84%). Dementia was reported in 74% patients, and Parkinsonism in 37%. Psychiatric features were reported in 44 out of 47 cases. Patients with chorea had lower expanded repeat lengths compared to patients without chorea. Eye movements were described in 19 cases, 8 were abnormal. Acanthocytes were detected in 4 of the 13 patients tested. Nineteen out of 20 MRIs were reported as abnormal with findings similar to HD. CONCLUSION: This review clarifies some aspects of the HDL2 phenotype and highlights others which require further investigation. Features that are unique to HDL2 have been documented in a minority of subjects and require prospective validation.

El volumen extracelular detecta la amiloidosis cardiaca y está correlacionado con el deterioro neurológico en la amiloidosis familiar relacionada con la transtiretina / Extracellular volume detects amyloidotic cardiomyopathy and correlates with neurological impairment in transthyretin-familial amyloidosis

INTRODUCCIÓN Y OBJETIVOS: La afección cardiaca determina el pronóstico y las opciones de tratamiento en la amiloidosis familiar relacionada con la transtiretina. Las técnicas de mapeo T1 de resonancia magnética cardiaca son útiles para determinar el volumen extracelular miocárdico. En este estudio se planteó la hipótesis de que el volumen extracelular miocárdico permite la identificación de la amiloidosis cardiaca y está correlacionado con el grado de deterioro neurológico en la amiloidosis familiar relacionada con la transtiretina. MÉTODOS: A un total de 31 pacientes con amiloidosis familiar relacionada con la transtiretina (19 varones; media de edad, 49 ± 12 años; 26 pacientes con la mutación Val30Met), se les realizaron estudios de mapeo T1 con resonancia magnética cardiaca y una evaluación neurológica con la Neuropathy Impairment Score of the Lower Limb, el cuestionario Norfolk Quality of Life y el índice de Karnofsky. RESULTADOS: Cinco pacientes tenían amiloidosis cardiaca (en todos los casos, confirmada mediante gammagrafía con 99mTc-DPD). El valor medio del volumen extracelular estaba aumentado en los pacientes con amiloidosis cardiaca (0,490 ± 0,131 frente a 0,289 ± 0,035; p = 0,026). El volumen extracelular mostró correlación con la edad (R = 0,467; p = 0,008), fracción aminoterminal del propéptido natriurético tipo B (Rs = 0,846; p < 0,001), el grosor máximo de la pared (R = 0,621; p < 0,001), el índice de masa ventricular izquierda (R = 0,685; p < 0,001), la fracción de eyección del ventrículo izquierdo (R = -0,378; p = 0,036), la puntuación de la Neuropathy Impairment Score of the Lower Limb (Rs = 0,604; p < 0,001), el cuestionario Norfolk Quality of Life (Rs = 0,529; p = 0,003) y el índice de Karnofsky (Rs = -0,517; p = 0,004). Se consideró que un valor de corte del volumen extracelular de 0,357 es diagnóstico de amiloidosis cardiaca con sensibilidad y especificidad del 100% (p < 0,001). El volumen extracelular y la fracción aminoterninal del propéptido natriurético tipo B son los únicos parámetros cardiacos que mostraron correlación significativa con las puntuaciones neurológicas. CONCLUSIONES: La cuantificación del volumen extracelular permite la identificación de la amiloidosis cardiaca y está correlacionada con el grado de deterioro neurológico en la amiloidosis familiar relacionada con la transtiretina. Esta técnica no invasiva puede ser un instrumento útil para el diagnóstico precoz de amiloidosis cardiaca y el seguimiento de la afección cardiaca y extracardiaca

INTRODUCTION AND OBJECTIVES: Cardiac involvement determines prognosis and treatment options in transthyretin-familial amyloidosis. Cardiac magnetic resonance T1 mapping techniques are useful to assess myocardial extracellular volume. This study hypothesized that myocardial extracellular volume allows identification of amyloidotic cardiomyopathy and correlates with the degree of neurological impairment in transthyretin-familial amyloidosis. METHODS: A total of 31 transthyretin-familial amyloidosis patients (19 mean age, 49 ± 12 years; 26 with the Val30Met mutation) underwent a T1 mapping cardiac magnetic resonance study and a neurological evaluation with Neuropathy Impairment Score of the Lower Limb score, Norfolk Quality of Life questionnaire, and Karnofsky index. RESULTS: Five patients had cardiac amyloidosis (all confirmed by 99mTc-DPD scintigraphy). Mean extracellular volume was increased in patients with cardiac amyloidosis (0.490 ± 0.131 vs 0.289 ± 0.035; P = .026). Extracellular volume correlated with age (R = 0.467; P = .008), N-terminal pro-B-type natriuretic peptide (RS = 0.846; P < .001), maximum wall thickness (R = 0.621; P < .001), left ventricular mass index (R = 0.685; P < .001), left ventricular ejection fraction (R = -0.378; P = .036), Neuropathy Impairment Score of the Lower Limb (RS = 0.604;P = .001), Norfolk Quality of Life questionnaire (RS = 0.529; P = .003) and Karnofsky index (RS= -0.517; P = .004). A cutoff value of extracellular volume of 0.357 was diagnostic of cardiac amyloidosis with 100% sensitivity and specificity (P < .001). Extracellular volume and N-terminal pro-B-type natriuretic peptide were the only cardiac parameters that significantly correlated with neurologic scores. CONCLUSIONS: Extracellular volume quantification allows identification of cardiac amyloidosis and correlates with the degree of neurological impairment in transthyretin-familial amyloidosis. This noninvasive technique could be a useful tool for early diagnosis of cardiac amyloidosis and to track cardiac and extracardiac amyloid disease

Progressive myoclonus epilepsy associated with neuroserpin inclusion bodies (neuroserpinosis).

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a conformational proteinopathy characterised by neuronal inclusion bodies composed of the serine protease inhibitor (SERPIN), neuroserpin. Presenting clinically as a familial dementia-epilepsy syndrome, the molecular mechanism of the pathogenic abnormalities in neuroserpin has been characterised at atomic resolution. There is a remarkable genotype-phenotype correlation between the degree of molecular destabilisation of the several variants of the neuroserpin protein, their propensity to self-associate and the age of onset of the dementia-epilepsy complex. As with other serpinopathies there appears to be a mix of cell-autonomous toxicity, due to neuronal accumulation of neuroserpin, and non-cell autonomous toxicity, caused by loss of protease inhibition, in this case the dysregulated protease is likely to be tissue plasminogen activator (tPA). FENIB should be considered in cases of progressive myoclonic epilepsy and dementia particularly where there is family history of neuropsychiatric disease.

SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.

Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause a relatively pure, slowly progressive cerebellar recessive ataxia mostly identified in Quebec, Canada. Combining next-generation sequencing techniques and deep-phenotyping (clinics, magnetic resonance imaging, positron emission tomography, muscle histology), we here established the frequency, phenotypic spectrum and genetic spectrum of SYNE1 in a screening of 434 non-Canadian index patients from seven centres across Europe. Patients were screened by whole-exome sequencing or targeted panel sequencing, yielding 23 unrelated families with recessive truncating SYNE1 mutations (23/434 = 5.3%). In these families, 35 different mutations were identified, 34 of them not previously linked to human disease. While only 5/26 patients (19%) showed the classical SYNE1 phenotype of mildly progressive pure cerebellar ataxia, 21/26 (81%) exhibited additional complicating features, including motor neuron features in 15/26 (58%). In three patients, respiratory dysfunction was part of an early-onset multisystemic neuromuscular phenotype with mental retardation, leading to premature death at age 36 years in one of them. Positron emission tomography imaging confirmed hypometabolism in extra-cerebellar regions such as the brainstem. Muscle biopsy reliably showed severely reduced or absent SYNE1 staining, indicating its potential use as a non-genetic indicator for underlying SYNE1 mutations. Our findings, which present the largest systematic series of SYNE1 patients and mutations outside Canada, revise the view that SYNE1 ataxia causes mainly a relatively pure cerebellar recessive ataxia and that it is largely limited to Quebec. Instead, complex phenotypes with a wide range of extra-cerebellar neurological and non-neurological dysfunctions are frequent, including in particular motor neuron and brainstem dysfunction. The disease course in this multisystemic neurodegenerative disease can be fatal, including premature death due to respiratory dysfunction. With a relative frequency of ∼5%, SYNE1 is one of the more common recessive ataxias worldwide.

Navajo Neurohepatopathy : A Case Report and Literature Review Emphasizing Clinicopathologic Diagnosis.

Navajo Neurohepatopathy (NNH) is a rare hepatocerebral mitochondrial DNA (mtDNA) depletion syndrome (MDS) with nonspecific clinical or pathologic features aside from Navajo ancestry. Because of the rarity of NNH, diagnosis rests on close clinicopathologic correlation and appropriate tissue triage for quantitative mtDNA analysis. We present a new case of NNH in which the clinical presentation and H&E liver biopsy histology indicated the need for NNH workup. Quantitative analysis of mtDNA in liver tissue was significantly reduced, and mutational analysis of the MPV17 gene confirmed homozygosity for the NNH-associated missense mutation, R50Q. The patient is now one year post liver transplant and continues to have normal liver function tests but suffers multiple immunosuppression-associated co-morbidities. A comprehensive literature review is provided to assist in diagnosis and management of NNH. (Acta gastroenterol. belg., 2016, 79, 463-469).

Long-Term Observations in an Affected Family with Neurogenic Scapuloperoneal Syndrome Caused by Mutation R269C in the TRPV4 Gene.

Mutations in the TRPV4 gene, encoding a polymodal Ca(2+) permeable channel, are causative for several human diseases, affecting the skeletal and the peripheral nervous system with highly variable phenotypes. We report on a family with two affected individuals. The father clinically suffered from a classical scapuloperoneal syndrome, while the son presented with a severe neonatal onset with congenital respiratory distress, feeding problems and arthrogryposis multiplex. Multi-Gene Panel sequencing by next generation sequencing revealed the heterozygous mutation c.805C>T (p.R269C) in the TRPV4 gene. Long-term observation over two decades showed no relevant disease progression in the father and, after a dramatic neonatal period, a significant improvement in the son who became ambulant with orthoses at the age of 5 years, suggesting a reasonably good prognosis even in cases with severe neonatal onset. Long-term findings in muscle ultrasound correlated with the clinical course, showing stable or even slightly improved findings. Neurography revealed a late-onset sensory neuropathy in the father, which was so far not described in TRPV4 neuropathies.

Neuroimaging studies and whole exome sequencing of PLA2G6-associated neurodegeneration in a family with intrafamilial phenotypic heterogeneity.

BACKGROUND: PLA2G6-associated neurodegeneration (PLAN) encompasses infantile- or atypical neuroaxonal dystrophy, and adult-onset dystonia-parkinsonism. Examination of the intrafamilial phenotypic variability of PLAN by neuroimaging data and background genetic differences has not been reported. METHODS: We report clinical, genetic (whole exome sequencing data), and neuroimaging findings from a Korean PLAN family showing intrafamilial phenotypic variability. Non-synonymous single nucleotide variants (SNVs) in Mendelian disorder genes related to parkinsonism, dystonia, ataxia, dementia or neurodegeneration with brain iron accumulation were compared between affected siblings. RESULTS: The proband presented with adult-onset dystonia-parkinsonism, whereas the affected brother presented with childhood-onset atypical neuroaxonal dystrophy. In the proband, an [18F]FP-CIT PET study showed markedly reduced uptake in the whole putamen, but fluid attenuated inversion recovery and gradient echo MRI studies revealed mild hypointensities in the substantia nigra and the putamen and severe hypointensities in the pallidum. On the other hand, in the affected brother, MRI scans showed severe hypointensities in the substantia nigra and the pallidum, and a [18F]-FP-CIT PET scan was normal. Analysis of the non-synonymous SNVs that were not shared between the two family members revealed non-synonymous SNVs related to parkinsonism including a novel heterozygous mutation (p.T44N) in FBX07 (PARK15) only in the proband, and non-synonymous SNVs related to neurodegeneration with brain iron accumulation in the affected brother. CONCLUSION: Our data suggests that dopaminergic neuronal degeneration may not secondary to iron accumulation in PLAN. The burden of pathogenic SNVs may influence the intrafamilial phenotypic variability of PLAN.