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. Symptoms that begin later, typically progress insidiously over a number of years. Genetic testing is able to confirm the diagnosis for many subjects. Insights from gene discovery indicate that abnormalities in diverse molecular processes underlie various forms of HSP, including disturbance in axon transport, endoplasmic reticulum morphogenesis, vesicle transport, lipid metabolism, and mitochondrial function. Pathologic studies in "uncomplicated" HSP have shown axon degeneration particularly involving the distal ends of corticospinal tracts and dorsal column fibers. Treatment is limited to symptom reduction including amelioration of spasticity, reducing urinary urgency, proactive physical therapy including strengthening, stretching, balance, and agility exercise.

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. RESULTS: We report the clinical and molecular spectrum of 40 patients with heterozygous pathogenic de novo variants in SPAST (age range: 2.2-27.7 years). We identified 19 unique variants (16/40 carried the same recurrent variant, p.Arg499His). Symptom onset was in early childhood (median: 11.0 months, interquartile range: 6.0 months) with significant motor and speech delay, followed by progressive ascending spasticity, dystonia, neurogenic bladder dysfunction, gastrointestinal dysmotility, and epilepsy. The mean Spastic Paraplegia Rating Scale score was 32.8 ± 9.7 (standard deviation). CONCLUSIONS: These results confirm that de novo variants in SPAST lead to a severe and complex form of HSP that differs from classic familial pure HSP-SPAST. Clinicians should be aware of this syndrome in the differential diagnosis for cerebral palsy. © 2022 International Parkinson and Movement Disorder Society.

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. The value of classifying disorders as inherited myelopathies lies primarily in facilitating their clinical recognition and differential diagnosis. It is useful to recognize that many hereditary myelopathies conform to one of four clinical paradigms: (1) spinocerebellar ataxia, (2) motor neuron disorder, (3) leukodystrophy, or (4) distal motor-sensory axonopathy predominantly affecting the central nervous system. Although they are myelopathies, spinal dysraphisms such as spina bifida and myelomeningocele are not included in this context because they are not usually due to single-gene mutation and have low hereditability. SUMMARY: This article illustrates clinical paradigms of hereditary myelopathy with clinical examples emphasizing the spectrum, clinical recognition, and differential diagnosis of hereditary myelopathies.

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. We report an individual in which DiGeorge syndrome was associated with progressive spastic paraparesis. This report extends the clinical phenotype of DiGeorge syndrome and presents the differential diagnosis of progressive spastic paraparesis in individuals with DiGeorge syndrome which provides insight into the clinical evaluation of such individuals.

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). Moreover, conditional knockout of NTE in the mouse CNS produces vacuolation and other degenerative changes in large neurons in the hippocampus, thalamus, and cerebellum, along with degeneration and swelling of axons in ascending and descending spinal cord tracts. In humans, NTE mutations cause a variety of neurodegenerative conditions resulting in a range of deficits including spastic paraplegia and blindness. Mutations in the Drosophila NTE orthologue SwissCheese (SWS) produce neurodegeneration characterized by vacuolization that can be partially rescued by expression of wild-type human NTE, suggesting a potential therapeutic approach for certain human neurological disorders. This chapter defines NTE and OPIDN, presents an overview of OP compounds, provides a rationale for NTE research, and traces the history of discovery of NTE and its relationship to OPIDN. It then briefly describes subsequent studies of NTE, including practical applications of the assay; aspects of its domain structure, subcellular localization, and tissue expression; abnormalities associated with NTE mutations, knockdown, and conventional or conditional knockout; and hypothetical models to help guide future research on elucidating the role of NTE in OPIDN.

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. Current diagnostic criteria for PLS may be a barrier to therapeutic development, requiring long delays between symptom onset and formal diagnosis. While new technologies sensitive to both upper and lower motor neuron involvement may ultimately resolve controversies in the diagnosis of PLS, we present updated consensus diagnostic criteria with the aim of reducing diagnostic delay, optimising therapeutic trial design and catalysing the development of disease-modifying therapy.

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. Mills' Syndrome is a rare unilateral variant of primary lateral sclerosis. Cognitive and behavioral involvement may occur.

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. We investigated sws5 flies and show for the first time that this allele causes progressive vacuolar formation in the brain and progressive deterioration of negative geotaxis speed and endurance. We demonstrate that inducible, neuron-specific expression of full-length human wildtype NTE reduces vacuole formation and substantially rescues mobility. Indeed, neuron-specific expression of wildtype human NTE is capable of rescuing mobility defects after 10 days of adult life at 29°C, when significant degeneration has already occurred, and significantly extends longevity of mutants at 25°C. These results raise the exciting possibility that late induction of NTE function may reduce or ameliorate neurodegeneration in humans even after symptoms begin. In addition, these results highlight the utility of negative geotaxis endurance as a new assay for longitudinal tracking of degenerative phenotypes in Drosophila.

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. METHODS: Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines. RESULTS: Eight mutations in six families with Oliver-McFarlane or Laurence-Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver-McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver-McFarlane and Laurence-Moon syndromes revealed extensive cerebellar degeneration and atrophy. CONCLUSIONS: Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon-Holmes syndrome and Boucher-Neuhäuser syndromes. Discovery of these additional PNPLA6-opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance.

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. In this review, the author highlights the clinical and genetic features of HSP.

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. Diverse combinations of exons are deleted or duplicated, highlighting the importance of particular exons for spastin function. Of the 54 CNVs, 38 (70%) appear to be mediated by an Alu-based mechanism, suggesting that the Alu-rich genomic architecture of SPAST renders this locus susceptible to various genome rearrangements. Analysis of breakpoint Alus further informs a model of Alu-mediated CNV formation characterized by small CNV size and potential involvement of mechanisms other than homologous recombination. Twelve deletions (22%) overlap part of SPAST and a portion of a nearby, directly oriented gene, predicting novel chimeric genes in these subjects' genomes. cDNA from a subject with a SPAST final exon deletion contained multiple SPAST:SLC30A6 fusion transcripts, indicating that SPAST CNVs can have transcriptional effects beyond the gene itself. SLC30A6 has been implicated in Alzheimer disease, so these fusion gene data could explain a report of spastic paraplegia and dementia cosegregating in a family with deletion of the final exon of SPAST. Our findings provide evidence that the Alu genomic architecture of SPAST predisposes to diverse CNV alleles with distinct transcriptional--and possibly phenotypic--consequences. Moreover, we provide further mechanistic insights into Alu-mediated copy-number change that are extendable to other loci.

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. The standard animal model of OPIDN is the adult hen, but its large size and high husbandry costs make this species a burdensome model for assessing neuropathic potential. Although the mouse does not readily exhibit clinical signs of OPIDN, it displays axonal lesions and expresses brain AChE and NTE. Therefore, the present research was performed as a further test of the hypothesis that inhibition of mouse brain AChE and NTE could be used to assess neuropathic potential using mouse brain preparations in vitro or employing mouse brain assays following dosing of OP compounds in vivo. Excellent correlations were obtained for inhibition kinetics in vitro of mouse brain enzymes vs. hen brain and human recombinant enzymes. Furthermore, inhibition of mouse brain AChE and NTE after dosing with OP compounds afforded ED(50) ratios that agreed with relative inhibitory potencies assessed in vitro. Taken together, results with mouse brain enzymes demonstrated consistent correspondence between in vitro and in vivo predictors of neuropathic potential, thus adding to previous studies supporting the validity of a mouse model for biochemical assessment of the ability of OP compounds to produce OPIDN.

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 1.2 to 9.6 per 100,000. Symptoms may begin at any age. Gait impairment that begins after childhood usually worsens very slowly over many years. Gait impairment that begins in infancy and early childhood may not worsen significantly. Postmortem studies consistently identify degeneration of corticospinal tract axons (maximal in the thoracic spinal cord) and degeneration of fasciculus gracilis fibers (maximal in the cervico-medullary region). HSP syndromes thus appear to involve motor-sensory axon degeneration affecting predominantly (but not exclusively) the distal ends of long central nervous system (CNS) axons. In general, proteins encoded by HSP genes have diverse functions including (1) axon transport (e.g. SPG30/KIF1A, SPG10/KIF5A and possibly SPG4/Spastin); (2) endoplasmic reticulum morphology (e.g. SPG3A/Atlastin, SPG4/Spastin, SPG12/reticulon 2, and SPG31/REEP1, all of which interact); (3) mitochondrial function (e.g. SPG13/chaperonin 60/heat-shock protein 60, SPG7/paraplegin; and mitochondrial ATP6); (4) myelin formation (e.g. SPG2/Proteolipid protein and SPG42/Connexin 47); (5) protein folding and ER-stress response (SPG6/NIPA1, SPG8/K1AA0196 (Strumpellin), SGP17/BSCL2 (Seipin), "mutilating sensory neuropathy with spastic paraplegia" owing to CcT5 mutation and presumably SPG18/ERLIN2); (6) corticospinal tract and other neurodevelopment (e.g. SPG1/L1 cell adhesion molecule and SPG22/thyroid transporter MCT8); (7) fatty acid and phospholipid metabolism (e.g. SPG28/DDHD1, SPG35/FA2H, SPG39/NTE, SPG54/DDHD2, and SPG56/CYP2U1); and (8) endosome membrane trafficking and vesicle formation (e.g. SPG47/AP4B1, SPG48/KIAA0415, SPG50/AP4M1, SPG51/AP4E, SPG52/AP4S1, and VSPG53/VPS37A). The availability of animal models (including bovine, murine, zebrafish, Drosophila, and C. elegans) for many types of HSP permits exploration of disease mechanisms and potential treatments. This review highlights emerging concepts of this large group of clinically similar disorders.

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.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain.

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. His pioneering work on OP neuropathy led to the view that the biochemical lesion consisted of NTE that had undergone OP inhibition and aging. Indeed, nonaging NTE inhibitors failed to produce disease but protected against neuropathy from subsequently administered aging inhibitors. Thus, inhibition of NTE activity was not the culprit; rather, formation of an abnormal protein was the agent of the disorder. More recently, however, Paul Glynn and colleagues showed that whereas conventional knockout of the NTE gene was embryonic lethal, conditional knockout of central nervous system NTE produced neurodegeneration, suggesting to these authors that the absence of NTE rather than its presence in some altered form caused disease. We now know that NTE is the 6th member of a 9-protein family called patatin-like phospholipase domain-containing proteins, PNPLA1-9. Mutations in the catalytic domain of NTE (PNPLA6) are associated with a slowly developing disease akin to OP neuropathy and hereditary spastic paraplegia called NTE-related motor neuron disorder (NTE-MND). Furthermore, the NTE protein from affected individuals has altered enzymological characteristics. Moreover, closely related PNPLA7 is regulated by insulin and glucose. These seemingly disparate findings are not necessarily mutually exclusive, but we need to reconcile recent genetic findings with the historical body of toxicological data indicating that inhibition and aging of NTE are both necessary in order to produce neuropathy from exposure to certain OP compounds. Solving this mystery will be satisfying in itself, but it is also an enterprise likely to pay dividends by enhancing our understanding of the physiological and pathogenic roles of the PNPLA family of proteins in neurological health and disease, including a potential role for NTE in diabetic neuropathy.

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. Whole-genome sequencing identified compound heterozygous mutations in the SPR gene encoding sepiapterin reductase. Disruption of SPR causes a decrease in tetrahydrobiopterin, a cofactor required for the hydroxylase enzymes that synthesize the neurotransmitters dopamine and serotonin. Supplementation of l-dopa therapy with 5-hydroxytryptophan, a serotonin precursor, resulted in clinical improvements in both twins.

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. To facilitate the collection of DNA sequence variation pertaining to neurogenetic disorders, we have initiated the "Neurogenetics Consortium" under the umbrella of the Human Variome Project. The Consortium's founding group consisted of basic researchers, clinicians, informaticians and database creators. This report outlines the strategic aims established at the preliminary meetings of the Neurogenetics Consortium and calls for the involvement of the wider neurogenetic community in enabling the development of this important resource.

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. NTE-MND resembles Troyer syndrome, except that short stature, cognitive impairment, and dysmorphic features, which often accompany Troyer syndrome, are not features of NTE-MND. Early onset, symmetry, and slow progression distinguish NTE-MND from typical amyotrophic lateral sclerosis. NTE is implicated in organophosphorus compound-induced delayed neurotoxicity (OPIDN). NTE-MND patients have upper and lower motor neuron deficits that are similar to OPIDN. Motor neuron degeneration in subjects with NTE mutations supports the role of NTE and its biochemical cascade in the molecular pathogenesis of OPIDN and possibly other degenerative neurologic disorders.