The hereditary spastic paraplegias.

The hereditary spastic paraplegias (HSPs) are a group of more than 90 genetic disorders in which lower extremity spasticity and weakness are either the primary neurologic impairments ("uncomplicated HSP") or when accompanied by other neurologic deficits ("complicated HSP"), important features of the clinical syndrome. Various genetic types of HSP are inherited such as autosomal dominant, autosomal recessive, X-linked, and maternal (mitochondrial) traits. Symptoms that begin in early childhood may be nonprogressive and resemble spastic diplegic cerebral palsy.

Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST.

Background: Familial hereditary spastic paraplegia (HSP)-SPAST (SPG4) typically presents with a pure HSP phenotype.

Objective: The aim of this study was to delineate the genotypic and phenotypic spectrum of children with de novo HSP-SPAST.

Methods: This study used a systematic cross-sectional analysis of clinical and molecular features.

Fever-Associated Seizures or Epilepsy: An Overview of Old and Recent Literature Acquisitions.

In addition to central nervous system infections, seizures and fever may occur together in several neurological disorders. Formerly, based on the clinical features and prognostic evolution, the co-association of seizure and fever included classical febrile seizures (FS) divided into simple, complex, and prolonged FS (also called febrile status epilepticus). Later, this group of disorders has been progressively indicated, with a more inclusive term, as "fever-associated seizures or epilepsy" (FASE) that encompasses: (a) FS divided into simple, complex, and prolonged FS; (b) FS plus; (c) severe myoclonic epilepsy in infancy (Dravet syndrome); (d) genetic epilepsy with FS plus; and (e) febrile infection-related epilepsy syndrome (FIRES).

The clinical spectrum of primary lateral sclerosis.

Primary lateral sclerosis is a distinct entity that has recently been classified as a "restricted phenotype" of ALS. It is characterized by a pattern of isolated upper motor neuron involvement that often begins in the legs and spreads diffusely. Distinction from other conditions requires careful consideration of clinical presentation and time course of disease.

Hereditary Myelopathies.

Purpose Of Review: This article guides clinicians in the clinical recognition and differential diagnosis of hereditary myelopathies.

Recent Findings: Rather than a disease, a disease process, or relating to specific cellular vulnerability, the term hereditary myelopathy refers to diverse inherited disorders in which major aspects of the clinical syndrome reflect disturbance of elements within the spinal cord (specifically, the dorsal columns and dorsal root ganglia, corticospinal tracts, and anterior horn cells). It is important to note that the clinical features of almost all hereditary myelopathies reflect not only disturbance of elements within the spinal cord but also disturbance of extraspinal structures (particularly, but not limited to, peripheral nerves and the cerebellum) and that these extraspinal clinical features can be very helpful in recognizing specific myelopathy syndromes.

An Unexplained Case of Progressive Spastic Paraparesis in an Individual with Known DiGeorge Syndrome.

DiGeorge syndrome (22q11.2 deletion) is associated with several neurologic disorders including structural abnormalities involving brain and spine, movement disorders, and epilepsy. Progressive spastic paraparesis has not been reported with DiGeorge syndrome.

Neuropathy target esterase (NTE/PNPLA6) and organophosphorus compound-induced delayed neurotoxicity (OPIDN).

Systemic inhibition of neuropathy target esterase (NTE) with certain organophosphorus (OP) compounds produces OP compound-induced delayed neurotoxicity (OPIDN), a distal degeneration of axons in the central nervous system (CNS) and peripheral nervous system (PNS), thereby providing a powerful model for studying a spectrum of neurodegenerative diseases. Axonopathies are important medical entities in their own right, but in addition, illnesses once considered primary neuronopathies are now thought to begin with axonal degeneration. These disorders include Alzheimer's disease, Parkinson's disease, and motor neuron diseases such as amyotrophic lateral sclerosis (ALS).

Primary lateral sclerosis: consensus diagnostic criteria.

Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system. Characterised by a slowly progressive upper motor neuron syndrome, the diagnosis is clinical, after exclusion of structural, neurodegenerative and metabolic mimics. Differentiation of PLS from upper motor neuron-predominant forms of amyotrophic lateral sclerosis remains a significant challenge in the early symptomatic phase of both disorders, with ongoing debate as to whether they form a clinical and histopathological continuum.

Delayed Induction of Human NTE (PNPLA6) Rescues Neurodegeneration and Mobility Defects of Drosophila swiss cheese (sws) Mutants.

Human PNPLA6 gene encodes Neuropathy Target Esterase protein (NTE). PNPLA6 gene mutations cause hereditary spastic paraplegia (SPG39 HSP), Gordon-Holmes syndrome, Boucher-Neuhäuser syndromes, Laurence-Moon syndrome, and Oliver-McFarlane syndrome. Mutations in the Drosophila NTE homolog swiss cheese (sws) cause early-onset, progressive behavioral defects and neurodegeneration characterized by vacuole formation.

Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes.

Background: Oliver-McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence-Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause.

Hereditary spastic paraplegia: clinical principles and genetic advances.

Hereditary spastic paraplegia (HSP) refers to inherited disorders in which spastic gait is either the only feature or is a major syndrome feature. There are more than 70 genetic types of HSP. Neuropathological studies, albeit limited to only a few genetic types of HSP, have identified axon degeneration involving the distal ends of the corticospinal tracts and fasciculus gracilis fibers.

The Alu-rich genomic architecture of SPAST predisposes to diverse and functionally distinct disease-associated CNV alleles.

Intragenic copy-number variants (CNVs) contribute to the allelic spectrum of both Mendelian and complex disorders. Although pathogenic deletions and duplications in SPAST (mutations in which cause autosomal-dominant spastic paraplegia 4 [SPG4]) have been described, their origins and molecular consequences remain obscure. We mapped breakpoint junctions of 54 SPAST CNVs at nucleotide resolution.

Further studies toward a mouse model for biochemical assessment of neuropathic potential of organophosphorus compounds.

Inhibition and aging of neuropathy target esterase (NTE) by neuropathic organophosphorus (OP) compounds triggers OP compound-induced delayed neuropathy (OPIDN), whereas inhibition of acetylcholinesterase (AChE) produces cholinergic toxicity. The neuropathic potential of an OP compound is defined by its relative inhibitory potency toward NTE vs. AChE assessed by enzyme assays following dosing in vivo or after incubations of direct-acting compounds or active metabolites with enzymes in vitro.

Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms.

Hereditary spastic paraplegia (HSP) is a syndrome designation describing inherited disorders in which lower extremity weakness and spasticity are the predominant symptoms. There are more than 50 genetic types of HSP. HSP affects individuals of diverse ethnic groups with prevalence estimates ranging from 1.

Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.

We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.

Neuropathy target esterase (NTE): overview and future.

Neuropathy target esterase (NTE) was discovered by M.K. Johnson in his quest for the entity responsible for the striking and mysterious paralysis brought about by certain organophosphorus (OP) esters.

Whole-genome sequencing for optimized patient management.

Whole-genome sequencing of patient DNA can facilitate diagnosis of a disease, but its potential for guiding treatment has been under-realized. We interrogated the complete genome sequences of a 14-year-old fraternal twin pair diagnosed with dopa (3,4-dihydroxyphenylalanine)-responsive dystonia (DRD; Mendelian Inheritance in Man #128230). DRD is a genetically heterogeneous and clinically complex movement disorder that is usually treated with l-dopa, a precursor of the neurotransmitter dopamine.

Call for participation in the neurogenetics consortium within the Human Variome Project.

The rate of DNA variation discovery has accelerated the need to collate, store and interpret the data in a standardised coherent way and is becoming a critical step in maximising the impact of discovery on the understanding and treatment of human disease. This particularly applies to the field of neurology as neurological function is impaired in many human disorders. Furthermore, the field of neurogenetics has been proven to show remarkably complex genotype-to-phenotype relationships.

Motor neuron disease due to neuropathy target esterase gene mutation: clinical features of the index families.

Recently, we reported that mutations in the neuropathy target esterase (NTE) gene cause autosomal recessive motor neuron disease (NTE-MND). We describe clinical, neurophysiologic, and neuroimaging features of affected subjects in the index families. NTE-MND subjects exhibited progressive lower extremity spastic weakness that began in childhood and was later associated with atrophy of distal leg and intrinsic hand muscles.

Motor neuron disease due to neuropathy target esterase mutation: enzyme analysis of fibroblasts from human subjects yields insights into pathogenesis.

Recently, we identified neuropathy target esterase (NTE) mutation as the cause of an autosomal recessive motor neuron disease (NTE-MND). Subsequently, we showed that NTE-MND mutations reduced specific activity (SA) and altered inhibitory kinetics of NTE catalytic domain constructs. Recent preliminary results showed that NTE is expressed in cultured human skin fibroblasts, and others have used mutant forms of neuronal proteins expressed in fibroblasts as biomarkers of neurogenetic diseases.

Constructs of human neuropathy target esterase catalytic domain containing mutations related to motor neuron disease have altered enzymatic properties.

Neuropathy target esterase (NTE) is a phospholipase/lysophospholipase associated with organophosphorus (OP) compound-induced delayed neurotoxicity (OPIDN). Distal degeneration of motor axons occurs in both OPIDN and the hereditary spastic paraplegias (HSPs). Recently, mutations within the esterase domain of NTE were identified in patients with a novel type of HSP (SPG39) designated NTE-related motor neuron disease (NTE-MND).

Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin II. The denture cream is a primary source of excessive zinc.

Neurodegeneration of the central and peripheral nervous system associated with hypocupremia and hyperzincinemia has been widely recognized but the origin of high zinc remained unknown. Denture cream has been recently suggested as one possible source of zinc, but the frequency with which denture fixative alone accounts for this syndrome is unknown. We analyzed the origin of excessive zinc in eleven patients with a progressive myelopolyneuropathy and unexplained hypocupremia with hyperzincinemia.

Treatment of Wilson's disease with tetrathiomolybdate: V. Control of free copper by tetrathiomolybdate and a comparison with trientine.

It has become clear that serum "free" copper (the copper not bound to ceruloplasmin in the blood) is the copper causing copper toxicity in Wilson's disease. But up until now, free copper has not been closely followed during initiation of anticopper therapy in neurologically presenting patients. During this period of initial therapy, the future fate of these patients hangs in the balance-if they worsen neurologically as often happens with penicillamine or trientine therapy, many never recover.