FAHN/SPG35: a narrow phenotypic spectrum across disease classifications.

The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the 'WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers.

Hereditary spastic paraplegias: time for an objective case definition and a new nosology for neurogenetic disorders to facilitate biomarker/therapeutic studies.

INTRODUCTION: Hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders characterized by progressive lower limb weakness and spasticity as core symptoms of the degeneration of the corticospinal motor neurons. Even after exclusion of infectious and toxic mimickers of these disorders, the definitive diagnosis remains tricky, mainly in sporadic forms, as there is significant overlap with other disorders. Since their first description, various attempts failed to reach an appropriate classification. This was due to the constant expansion of the clinical spectrum of these diseases and the discovery of new genes, a significant number of them was involved in overlapping diseases. Areas covered: In this perspective review, an extensive literature study was conducted on the historical progress of HSP research. We also revised the previous and the current classifications of HSP and the closely related neurogenetic disorders and analyzed the areas of overlap. Expert opinion: There is undeniable need for objective case definition and reclassification of all neurogenetic disorders including HSPs, a prerequisite to improve patient follow-up, biomarker identification and develop therapeutics. The challenge is to understand why mutations can give rise to multiple phenotypic presentations along this spectrum of diseases in which the corticospinal tract is affected.

[Ataxias and hereditary spastic paraplegias]. / Ataxien und hereditäre spastische Spinalparalysen.

Hereditary ataxias and spastic paraplegias are genetic disorders with age-dependent nearly complete penetrance. The mostly monogenetic etiology allows one to establish the diagnosis, study pathogenesis and to develop new causative therapeutic approaches for these diseases. Both the causative genes as well as the clinical presentation overlap considerably between hereditary ataxias and spastic paraplegias. This strongly argues towards a united classification for these two groups of diseases. Next generation sequencing technologies have greatly expanded the number of genes known to be causative for hereditary ataxias and spastic paraplegias and allow simultaneous time- and cost-effective diagnostic testing of > 200 genes. However, repeat expansions and large genomic deletions must be considered separately. Here, we suggest a pragmatic algorithm for genetic testing in hereditary ataxias and spastic paraplegias that we have developed in our specialized outpatient clinics. Detailed phenotyping remains crucial to interpret the multitude of genetic variants discovered by high throughput sequencing techniques. Despite recent technical advances, a substantial proportion of ataxia and spastic paraplegia families are still without a molecular diagnosis. Beside new and so far undetected ataxia and spasticity genes, unusual mutation types including noncoding variants and polygenic inheritance patterns may contribute. Because of these clinical, genetic, and technological challenges, patients with hereditary ataxias and spastic paraplegias should be referred to specialized centers offering research and clinical studies. This will also help to recruit representative patient cohorts for upcoming interventional trials.

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways.

Autosomal-dominant spinocerebellar ataxias, autosomal-recessive spinocerebellar ataxias, and hereditary spastic paraplegias have traditionally been designated in separate clinicogenetic disease classifications. This classification system still largely frames clinical thinking and genetic workup in clinical practice. Yet, with the advent of next-generation sequencing, phenotypically unbiased studies have revealed the limitations of this classification system. Various genes (eg, SPG7, SYNE1, PNPLA6) traditionally rooted in either the ataxia or hereditary spastic paraplegia classification system have now been shown to cause ataxia on the one end of the disease continuum and hereditary spastic paraplegia on the other. Other genes such as GBA2 and KIF1C were almost simultaneously published as both a hereditary spastic paraplegia and an ataxia gene. The variability and fluidity of observed phenotypes along the ataxia-spasticity spectrum warrants a rethinking of the traditional classification system. We propose to replace this divisive diagnosis-driven ataxia and hereditary spastic paraplegia classification system by a descriptive, unbiased approach of modular phenotyping. This approach is also open to expansion of the phenotype beyond ataxia and spasticity, which often occur as part of broader multisystem neuronal dysfunction. The concept of a continuous ataxia-spasticity disease spectrum is further supported by ataxias and hereditary spastic paraplegias sharing not only overlapping phenotypes and underlying genes, but also common cellular pathways and disease mechanisms. This suggests a shared vulnerability of cerebellar and corticospinal neurons for common pathophysiological processes. It might be this mechanistic overlap that drives their clinical overlap. A mechanistically inspired classification system will help to pave the way for mechanism-based strategies for drug development. © 2017 International Parkinson and Movement Disorder Society.

Hereditary Spastic Paraplegia: Clinical and Genetic Hallmarks.

Hereditary spastic paraplegia comprises a wide and heterogeneous group of inherited neurodegenerative and neurodevelopmental disorders resulting from primary retrograde dysfunction of the long descending fibers of the corticospinal tract. Although spastic paraparesis and urinary dysfunction represent the most common clinical presentation, a complex group of different neurological and systemic compromise has been recognized recently and a growing number of new genetic subtypes were described in the last decade. Clinical characterization of individual and familial history represents the main step during diagnostic workup; however, frequently, few and unspecific data allows a low rate of definite diagnosis based solely in clinical and neuroimaging basis. Likewise, a wide group of neurological acquired and inherited disorders should be included in the differential diagnosis and properly excluded after a complete laboratorial, neuroimaging, and genetic evaluation. The aim of this review article is to provide an extensive overview regarding the main clinical and genetic features of the classical and recently described subtypes of hereditary spastic paraplegia (HSP).

Classifications of neurogenetic diseases: An increasingly complex problem.

Neurodegenerative disorders represent a wide group of diseases affecting the central and/or peripheral nervous system. Many of these disorders were described in the 19th century, but our genetic knowledge of them is recent (over the past 25 years). However, the continual discovery of disease-causing gene mutations has led to difficulties in the classification of these diseases. For this reason, our present proposals for updating and simplifying the classification of some of these conditions (Charcot-Marie-Tooth diseases, distal hereditary motor neuropathies, hereditary sensory and autonomic neuropathies, hereditary spastic ataxias, hereditary spastic paraplegias and hereditary spastic ataxias) are expounded here.

SCA1 patients may present as hereditary spastic paraplegia and must be included in spastic-ataxias group.

INTRODUCTION: The combination of cerebellar ataxia and spasticity is common. However, autosomal dominant genetic diseases presenting with spastic-ataxia are a smaller group. Pyramidal signs have been frequently observed in several SCA subtypes, particularly in spinocerebellar ataxia type 1. METHODS: We prospectively evaluated the pyramidal signs and spasticity in SCA1 patients, and correlated the data with genetic and clinical features. RESULTS: In this study, we observed that spasticity may be an early and presenting feature of SCA1, since 3 patients had pyramidal signs and spasticity as the first neurological sign. SCA1 patients with spasticity were significantly younger. CONCLUSION: SCA1 may rarely present with pure spastic paraplegia, resembling hereditary spastic paraplegia, before the appearance of cerebellar signs. This observation may confuse the neurologist when a genetic testing is requested for an autosomal dominant spastic paraplegia, directing research to hereditary spastic paraplegia group.

SPG35 contributes to the second common subtype of AR-HSP in China: frequency analysis and functional characterization of FA2H gene mutations.

Hereditary spastic paraplegias (HSPs) encompass a clinically and genetically heterogeneous group of neurodegenerative disorders. Recently, mutations in fatty acid 2-hydroxylase gene (FA2H) have been identified responsible for HSPs type 35 (SPG35). This study aims to define the contribution of FA2H to Chinese autosomal recessive HSP (AR-HSP) patients and provide insights into the enzymatic functions of the novel mutations. Direct sequencing of FA2H was conducted in 31 AR-HSP families and 55 sporadic cases without SPG11, SPG15, SPG5 and SPG7 gene mutations. Enzymatic activity of the mutated proteins was further examined. Three novel mutations were found in two Chinese families, including two compound heterozygous mutations (c.388C>T/p.L130F and c.506+6C>G) and one homozygous mutation (c.230T>G/p.L77R). The c.506+6C>G splice-site mutation led to the deletion of exon 3. Measurement of enzymatic functions revealed a significant reduction in the enzymatic activity of FA2H associated with p.L130F and p.L77R. Overall, our data widens the spectrum of the mutations on FA2H, and functional analyses indicate that these mutations severely impair the enzymatic activity of FA2H. Furthermore, frequency analysis shows that SPG35 is the second most common subtype of AR-HSP in China.

Clinical features and management of hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions.

Clinical features and management of hereditary spastic paraplegia / Aspectos clinicos e manejo das paraplegias espasticas hereditarias

Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions.

Paraplegias espásticas hereditárias (PEH) constituem um grupo de desordens geneticamente determinadas caracterizadas por espasticidade e paraparesia de progressão insidiosa. Paraplegia espástica aparentemente esporádica de início no adulto constitui problema frequente na prática neurológica. Evidências recentes sugerem que uma proporção significativa destes casos é geneticamente determinada. O grupo das PEH é dividido clinicamente em formas puras e complicadas de acordo com a concomitância de outras manifestações clinicas e neurológicas. Até o momento 60 tipos genéticos foram identificados. Todos os modos de herança monogênica já foram descritos: autossômica dominante, autossômica recessiva, ligada ao X e mitocondrial. Avanços recentes indicam que alterações do transporte axonal estão implicadas na degeneração dos longos axônios motores no sistema nervoso central na PEH. Nesta revisão abordamos recentes avanços na área com ênfase nos aspectos clínicos chave que ajudam o neurologista geral no diagnóstico e manejo correto deste grupo de doenças.

Paraplegia espástica familiar: atualização / Familiar spastic paraplegia: update

A Paraplegia Espástica Familiar (PEF) é uma doença hereditária com apresentações diversas, que variam desde a forma pura de apresentação clínica, caracterizada por fraqueza nos membros inferiores, espasticidade, aumento dos reflexos tendíneos, podendo apresentar clônus ou sinal de Babinski, urgência urinária e diminuição da sensibilidade vibratória nas extremidades dos membros inferiores, e a forma complexa de apresentação, que consiste no tipo puro acrescido de outros sinais e sintomas neurológicos. A forma de transmissão é por herança genética autossômica dominante, autossômica recessiva ou ligada ao cromossomo X, e o diagnóstico definitivo da forma clínica depende da realização dos testes genéticos, que identificam os alelos mutantes e suas respectivas proteínas transcritas, as quais participam no processo fisiopatológico da doença. O objetivo deste trabalho é de revisar as características clínicas e genéticas na PEF, as vias fisiopatológicas e o aconselhamento genético. Para isso, foi realizada uma revisão de 82 trabalhos que abordam temas relevantes sobre o assunto.

The Hereditary Spastic Paraplegia (HSP) is a degenerative disease with various presentations, ranging from the pure form of clinical presentation, characterized by weakness in the lower limbs, spasticity, increase of tendineous reflexes and clonus, Babinski sign, urinary urgency and diminished distal lower limbs vibratory sensation. There are two different forms of presentation: the pure form and other with different neurological symptoms and signs in addition to spastic paraplegia. The means of transmission is by genetic inheritance autosomal dominant, autosomal recessive or X cromosome-linked and the definitive diagnosis depends on the performance of genetic tests that identify mutant alleles and their proteins transcribed, participating in a major pathophysiological process of the disease. The purpose of this work is to review the clinical and genetics features in HSP, the pathophysiologic pathways and the genetic counseling. In order to learn more about this disease we reviewed data of 82 works that discuss relevant topics on this subject.

Expansion of the phenotypic spectrum of SPG6 caused by mutation in NIPA1.

BACKGROUND: Hereditary spastic paraplegia type 6 (SPG6) is caused by mutations in the NIPA1 gene, this is a rare cause of HSP, until now, all the affected individuals reported displayed "pure" spastic paraplegia. OBJECTIVES: To analyze the genotype/phenotype correlation of mutations so far described in NIPA1. METHODS: Eighty-six Chinese Han HSP patients were investigated for SPG6 mutations by direct sequencing of the NIPA1 gene. RESULTS: One heterozygous missense mutation c.316G>C/p.G106R was identified in a complicated form of ADHSP family with peripheral nerves disease, and SPG6 mutation in our sample accounted for 3.6% (1/28) of ADHSP families and 1.1% (1/86) of non-ARHSP patients who were negative for SPG4, SPG3A and SPG31 mutations. CONCLUSIONS: We report the first complicated case of SPG6 in the world by the presence of peripheral neuropathy, which extends the phenotype initially described.

Genetics and pathogenesis of inherited ataxias and spastic paraplegias.

Inherited ataxias and hereditary spastic paraplegias are two heterogeneous groups of neurodegenerative disorders with a wide spectrum of clinical symptoms and also, with a remarkable number of involved loci/genes. Inherited ataxias are clinically characterized by progressive degeneration of cerebellum and spinocerebellar tracts of the spinal cord associated with a variable combination of signs of central and peripheral nervous system. Hereditary spastic paraplegias (HSPs) are characterized by slowly progressive spasticity and weakness of lower limbs, due to pyramidal tract dysfunction. The classification of these diseases is extremely difficult because of overlapping symptoms among different clinical forms. For this reason, the genetic classification for both inherited ataxias and HSP forms, based on the causative loci/genes has reached general acceptance. The aim of this review is to summarize the genetics and the pathogenic mechanisms involved in these two groups of neurodegenerative spinocerebellar disorders.

Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous disorders characterized by progressive spasticity of the lower limbs. Mutations in the SPG4 gene, which encodes spastin protein, are responsible for up to 45% of autosomal dominant cases. OBJECTIVE: To search for disease-causing mutations in a large series of Italian patients with HSP. DESIGN: Samples of DNA were analyzed by direct sequencing of all exons in SPG4. Samples from a subset of patients were also analyzed by direct sequencing of all exons in SPG3A, SPG6, SPG10, and SPG13. SETTING: Molecular testing facility in Italy. PATIENTS: Sixty unrelated Italian patients with pure (n = 50) and complicated (n = 10) HSP. MAIN OUTCOME MEASURES: Mutations in SPG4, SPG3A, SPG6, SPG10, and SPG13. RESULTS: We identified 12 different mutations, 8 of which were novel, in 13 patients. No mutations of any of the other HSP genes tested were found in 15 patients with sporadic pure HSP who did not have mutations in the SPG4 gene. CONCLUSIONS: The overall rate of mutation in the SPG4 gene within our sample was 22%, rising to 26% when only patients with pure HSP were considered. The negative result obtained in 15 patients without mutations in SPG4 in whom 4 other genes were analyzed (SPG3A, SPG6, SPG10, and SPG13) indicate that these genes are not frequently mutated in sporadic pure HSP.

Traffic accidents: molecular genetic insights into the pathogenesis of the hereditary spastic paraplegias.

The hereditary spastic paraplegias (HSPs) comprise a clinically and genetically diverse group of inherited neurological disorders in which the primary manifestation is progressive spasticity and weakness of the lower limbs. The identification of over 25 genetic loci and 11 gene products for these disorders has yielded new insights into the molecular pathways involved in the pathogenesis of HSPs. In particular, causative mutations in proteins implicated in mitochondrial function, intracellular transport and trafficking, axonal development, and myelination have been identified. In many cases, the proper intracellular trafficking and distribution of molecules and organelles are ultimately thought to be involved in HSP pathogenesis. In fact, deficits in intracellular cargo trafficking and transport are concordant with the length dependence of the distal axonopathy of upper motor neurons observed in HSP patients. Through a better understanding of the functions of the HSP gene products, novel therapeutic targets for treatment and prevention are being identified.

Primary lateral sclerosis, hereditary spastic paraplegia and amyotrophic lateral sclerosis: discrete entities or spectrum?

Among the motor neuron diseases, three share the clinical features of prominent upper motor neuron signs--amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) and the hereditary spastic paraplegias (HSP). While genetic testing can assist in the identification of several variants of the latter, in the remaining cases, including those in which spasticity may be associated with amyotrophy, clinical differentiation of the three disorders may prove difficult. In this paper we review the evidence that these are distinct disorders and conclude that, for ALS and PLS particularly, there may be justification in considering them as single points along a continuum of multisystem disorders with conspicuous motor neuron involvement. Only through the development and application of exacting clinical diagnostic criteria to epidemiological studies, along with greater numbers of post-mortem examinations, however, will these questions be answered fully.

Advances in the hereditary spastic paraplegias.

This review summarizes advances in understanding the genetics of the hereditary spastic paraplegias (HSPs), a diverse group of inherited disorders in which the primary symptom is insidiously progressive difficulty walking due to lower extremity spastic weakness. Twenty HSP loci and nine HSP genes have been discovered. This progress has yielded new insights into the diverse molecular pathogenesis that underlies these clinically similar disorders.