Alu Retrotransposition Event in SPAST Gene as a Novel Cause of Hereditary Spastic Paraplegia.

OBJECTIVES: To diagnose the molecular cause of hereditary spastic paraplegia (HSP) observed in a four-generation family with autosomal dominant inheritance. METHODS: Multiplex ligation-dependent probe amplification (MLPA), whole-exome sequencing (WES), and RNA sequencing (RNA-seq) of peripheral blood leukocytes were performed. Reverse transcription polymerase chain reaction (RT-PCR) and Sanger sequencing were used to characterize target regions of SPAST. RESULTS: A 121-bp AluYb9 insertion with a 30-bp poly-A tail flanked by 15-bp direct repeats on both sides was identified in the edge of intron 16 in SPAST that segregated with the disease phenotype. CONCLUSIONS: We identified an intronic AluYb9 insertion inducing splicing alteration in SPAST causing pure HSP phenotype that was not detected by routine WES analysis. Our findings suggest RNA-seq is a recommended implementation for undiagnosed cases by first-line diagnostic approaches. © 2023 International Parkinson and Movement Disorder Society.

Long-read sequencing revealing intragenic deletions in exome-negative spastic paraplegias.

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and weakness in the lower extremities. To date, a total of 88 types of SPG are known. To diagnose HSP, multiple technologies, including microarray, direct sequencing, multiplex ligation-dependent probe amplification, and short-read next-generation sequencing, are often chosen based on the frequency of HSP subtypes. Exome sequencing (ES) is commonly used. We used ES to analyze ten cases of HSP from eight families. We identified pathogenic variants in three cases (from three different families); however, we were unable to determine the cause of the other seven cases using ES. We therefore applied long-read sequencing to the seven undetermined HSP cases (from five families). We detected intragenic deletions within the SPAST gene in four families, and a deletion within PSEN1 in the remaining family. The size of the deletion ranged from 4.7 to 12.5 kb and involved 1-7 exons. All deletions were entirely included in one long read. We retrospectively performed an ES-based copy number variation analysis focusing on pathogenic deletions, but were not able to accurately detect these deletions. This study demonstrated the efficiency of long-read sequencing in detecting intragenic pathogenic deletions in ES-negative HSP patients.

Copy number variations in SPAST and ATL1 are rare among Brazilians.

Copy number variations (CNV) may represent a significant proportion of SPG4 and SPG3A diagnosis, the most frequent autosomal dominant subtypes of hereditary spastic paraplegias (HSP). We aimed to assess the frequency of CNVs in SPAST and ATL1 and to update the molecular epidemiology of HSP families in southern Brazil. A cohort study that included 95 Brazilian index cases with clinical suspicion of HSP was conducted between April 2011 and September 2022. Multiplex Ligation Dependent Probe Amplification (MLPA) was performed in 41 cases without defined diagnosis by different massive parallel sequencing techniques (MPS). Diagnosis was obtained in 57/95 (60%) index cases, 15/57 (26.3%) being SPG4. Most frequent autosomal recessive HSP subtypes were SPG7 followed by SPG11, SPG76 and cerebrotendinous xanthomatosis. No CNVs in SPAST and ATL1 were found. Copy number variations are rare among SPG4 and SPG3A families in Brazil. Considering the possibility of CNVs detection by specific algorithms with MPS data, we consider that this is likely the most cost-effective approach to investigate CNVs in these genes in low-risk populations, with MLPA being reserved as an orthogonal confirmatory test.

Hereditary spastic paraplegia in Mali: epidemiological and clinical features.

BACKGROUND AND PURPOSE: Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases divided into pure and complex forms, with spasticity in lower limbs only, or associated with other neurologic and non-neurologic manifestations, respectively. Although widely reported in other populations, very little data exist in sub-Saharan Africa. METHODS: Patients with neurodegenerative features were evaluated over a 19-month period at the Department of Neurology, Teaching Hospital of Point "G", Bamako, Mali. The diagnosis of HSP was considered based on family history and the absence of other known non-genetic causes. Genetic analysis including candidate gene and whole exome sequencing was performed and variant pathogenicity was tested using prediction tools and ACMG guidelines. RESULTS: Of the 170 families with hereditary neurological disorders enrolled, 16 had features consistent with HSP, a frequency of 9%. The average age of onset was 14.7 years with 46% starting before age 6. The male/female ratio was 2.6:1. Complex forms were seen in 75% of cases, and pure forms in 25%. Pyramidal findings were present in all patients. Associated features included mental retardation, peripheral neuropathy, epilepsy, oculomotor impairment and urinary urgency. Most patients were treated with a muscle relaxant and physical therapy, and restorative surgery was done in one. Genetic testing identified novel variants in three families (19%). CONCLUSION: This study confirms the clinical variability of HSPs and adds African data to the current literature.

Previously Undescribed Gross HACE1 Deletions as a Cause of Autosomal Recessive Spastic Paraplegia.

Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS, OMIM 616756) is a rare genetic disease caused by biallelic pathogenic variants in the HACE1 gene. Originally, these mutations have been reported to be implicated in tumor predisposition. Nonetheless, via whole exome sequencing in 2015, HACE1 mutations were suggested to be the cause of a new autosomal recessive neurodevelopmental disorder, which is characterized by spasticity, muscular hypotonia, and intellectual disability. To date, 14 HACE1 pathogenic variants have been described; these variants have a loss-of-function effect that leads to clinical presentations with variable severities. However, gross deletions in the HACE1 gene have not yet been mentioned as a cause of spastic paraplegia. Here, we report a clinical case involving a 2-year-old male presenting with spasticity, mainly affecting the lower limbs, and developmental delay. Exome sequencing, chromosomal microarray analysis, and mRNA analysis were used to identify the causative gene. We revealed that the clinical findings were due to previously undescribed HACE1 biallelic deletions. We identified the deletion of exon 7: c.(534+1_535-1)_(617+1_618-1)del (NM_020771.4) and the gross deletion in the 6q16.3 locus, which affected the entire HACE1 gene: g.105018931_105337494del, (GRCh37). A comprehensive diagnostic approach for the patients with originally homozygous mutations in HACE1 is required since false homozygosity results are possible. More than 80% of the described mutations were reported to be homozygous. Initial hemizygosity is hard to detect by quantitative methods, and this may challenge molecular diagnostic identification in patients with spastic paraplegia.

Genetic, structural and clinical analysis of spastic paraplegia 4.

INTRODUCTION: Spastic paraplegia type 4 (SPG4), resulting from heterozygous mutations in the SPAST gene, is the most common form among the heterogeneous group of hereditary spastic paraplegias (HSPs). We aimed to study genetic and clinical characteristics of SPG4 across Canada. METHODS: The SPAST gene was analyzed in a total of 696 HSP patients from 431 families by either HSP-gene panel sequencing or whole exome sequencing (WES). We used Multiplex ligation-dependent probe amplification to analyze copy number variations (CNVs), and performed in silico structural analysis of selected mutations. Clinical characteristics of patients were assessed, and long-term follow-up was done to study genotype-phenotype correlations. RESULTS: We identified 157 SPG4 patients from 65 families who carried 41 different SPAST mutations, six of which are novel and six are CNVs. We report novel aspects of mutations occurring in Arg499, a case with homozygous mutation, a family with probable compound heterozygous mutations, three patients with de novo mutations, three cases with pathogenic synonymous mutation, co-occurrence of SPG4 and clinically isolated syndrome, and novel or rarely reported signs and symptoms seen in SPG4 patients. CONCLUSION: Our study demonstrates that SPG4 is a heterogeneous type of HSP, with diverse genetic features and clinical manifestations. In rare cases, biallelic inheritance, de novo mutation, pathogenic synonymous mutations and CNVs should be considered.

Inherited metabolic diseases mimicking hereditary spastic paraplegia (HSP): a chance for treatment.

The syndromic group of hereditary spastic paraplegias has a heterogeneous clinical profile and a broad differential diagnosis, including neurometabolic disorders that are potentially treatable. This group includes 5,10-methylenetetrahydrofolate reductase deficiency, cobalamin C deficiency disease, dopamine responsive dystonia, cerebrotendinous xanthomatosis, biotinidase deficiency, GLUT1 deficiency syndrome, delta-e-pyrroline-carboxylase-synthetase deficiency, hyperonithinemia-hyperammonemia-homocitrullinuria syndrome, arginase deficiency, multiple carboxylase deficiency, and X-linked adrenoleukodystrophy. This review describes these diseases in detail, highlighting the importance of early diagnosis and effective treatment aiming at preserving functionality and quality of life in these patients. For the purpose of this study, we carried a non-systematic review on PUBMED, finding an initial sample of 122 papers; upon refining, 41 articles were found relevant to this review. Subsequently, we added review articles and works with historical relevance, totalizing 76 references. An adequate diagnostic workup in patients presenting with spastic paraplegia phenotype should include screening for these rare conditions, followed by parsimonious ancillary investigation.

A case of spastic paraplegia type 11 mimicking a GM2-gangliosidosis.

INTRODUCTION: Spastic paraplegia type 11 (SPG11) is the most frequent autosomal recessive HSP. Studies on SPG11 patients' fibroblasts, post-mortem brains, and mouse models revealed endolysosomal system dysfunction and lipid accumulation, especially gangliosides. We report a patient with early clinical findings mimicking a GM2-gangliosidosis. METHODS: A clinical, biochemical, and metabolic characterization was performed. Electron microscopy analysis was completed on rectal mucosa and skin biopsy specimens. A NGS panel of genes associated to neuronal ceroid lipofuscinosis and HSP was analyzed. RESULTS: The patient presented with worsening walking difficulty and psychomotor slowdown since childhood; to exclude a neurometabolic storage disease, skin and rectal biopsies were performed: enteric neurons showed lipofuscin-like intracellular inclusions, thus suggesting a possible GM2-gangliosidosis. However, further analysis did not allow to confirm such hypothesis. In adulthood we detected flaccid paraplegia, nystagmus, axonal motor neuropathy, carpus callosum atrophy, and colon atony. Surprisingly, the NGS panel detected two already reported SPG11 mutations in compound heterozygosity. CONCLUSIONS: We describe for the first time pathological hallmarks of SPG11 in enteric neuron from a rectal mucosa biopsy. The report illustrates the possible overlap between SPG11 and GM2-gangliosidosis, especially in the first disease phases and helps to improve our knowledge about SPG11 physiopathology.

Hartnup disease presenting as hereditary spastic paraplegia and severe peripheral neuropathy.

Hartnup disease cases were rare, and the genotype-phenotype correlation was not fully understood. Here we reported two unrelated young men diagnosed as Hartnup disease, who carried novel compound heterozygote mutations in the SLC6A19 gene and presented with new phenotypes. Other than intermittent encephalopathy and photosensitive rashes, they displayed symptoms and signs of spastic paraplegia and severe peripheral nerve damages. Magnetic resonance imaging showed mild bilateral cerebellar atrophy and thinning of the thoracic spinal cord. Electromyogram detected mixed sensorimotor polyneuropathy in lower limbs. Sural nerve biopsy and pathological study indicated the moderately reduced neural fibers in the periphery nerves. Urinary amino acid analysis showed increased levels of multiple neutral amino acids. Moreover, muscle strengths in the lower limbs and the walking ability have been improved in both cases (MRC 3/5 to 4/5 in Patient 1; walking distance elongated from 50 to 100 m in Patient 2) after the treatment with oral nicotinic acid and intravenous injection of multiple amino acids. Exome sequencing revealed and confirmed the existence of the novel compound heterozygous SLC6A19 mutations: c.533G>A (p.Arg178Gln) and c.1379-1G>C mutations in patient1, and c.1433delG (p.Gly478AlafsTer44) and c.811G>A (p.Ala271Thr) in patient 2. Taken together, these findings expanded the clinical, neuroimaging, pathology, and genetic spectrum of Hartnup disease. However, the co-existence of HSP and peripheral neuropathy was only inferred based on clinical observations, and pathological and molecular studies are needed to further dissect the underlying mechanisms.

Autosomal dominant ADAR c.3019G>A (p.(G1007R)) variant is an important mimic of hereditary spastic paraplegia and cerebral palsy.

BACKGROUND: The type 1 interferonopathy, Aicardi-Goutières syndrome 6 (AGS6), is classically caused by biallelic ADAR mutations whereas dominant ADAR mutations are associated with dyschromatosis symmetrica hereditaria (DSH). The unique dominant ADAR c.3019G>A variant is associated with neurological manifestations which mimic spastic paraplegia and cerebral palsy (CP). CASE SUMMARIES: We report three cases of spastic paraplegia or CP diagnosed with AGS6 caused by the ADAR c.3019G>A variant. Two children inherited the variant from an asymptomatic parent, and each child had a different clinical course. The youngest case demonstrated relentless progressive symptoms but responded to immunomodulation using steroids and ruxolitinib. CONCLUSION: The ADAR c.3019G>A variant has incomplete penetrance and is a likely underrecognized imitator of spastic paraplegia and dystonic CP. A high level of clinical suspicion is required to diagnose this form of AGS, and disease progression may be ameliorated by immunomodulatory treatment with selective Janus kinase inhibitors.

Childhood-onset hereditary spastic paraplegia and its treatable mimics.

Early-onset forms of hereditary spastic paraplegia and inborn errors of metabolism that present with spastic diplegia are among the most common "mimics" of cerebral palsy. Early detection of these heterogenous genetic disorders can inform genetic counseling, anticipatory guidance, and improve outcomes, particularly where specific treatments exist. The diagnosis relies on clinical pattern recognition, biochemical testing, neuroimaging, and increasingly next-generation sequencing-based molecular testing. In this short review, we summarize the clinical and molecular understanding of: 1) childhood-onset and complex forms of hereditary spastic paraplegia (SPG5, SPG7, SPG11, SPG15, SPG35, SPG47, SPG48, SPG50, SPG51, SPG52) and, 2) the most common inborn errors of metabolism that present with phenotypes that resemble hereditary spastic paraplegia.

Health service experiences among adults with hereditary spastic paraparesis or neurofibromatosis type 1.

BACKGROUND: Persons with rare disorders may experience poorer health services due to limited knowledge about rare disorders among health professionals. Knowledge about how persons with rare disorders perceive health services can help inform service providers to enhance their practices. METHODS: We conducted a self-report survey among adults with the rare disorders hereditary spastic paraparesis (HSP; n = 108; mean age 57.7 years; 54.2% females) and neurofibromatosis type 1 (NF1, n = 142; mean age = 50.3 years; 62.0% females). Their responses concerning perceived health experiences were compared to healthy controls from the population study HUNT-3 (n = 7,312). RESULTS: Both rare disorder groups reported lower satisfaction, trust, and participation in meetings with their general practitioner and specialist health services. More reported health problems were overall associated with poorer health service experiences. CONCLUSION: There is a need to identify predictors of health service experiences at the patient and health service provider levels with the aim to tighten the gap between the health experiences of patients with and without rare disorders.

X-linked myotubular myopathy mimics hereditary spastic paraplegia in two female manifesting carriers of pathogenic MTM1 variant.

X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy caused by pathogenic variants in the myotubularin 1 (MTM1) gene. XLMTM leads to severe weakness in male infants and majority of them die in the early postnatal period due to respiratory failure. Disease manifestations in female carriers vary from asymptomatic to severe, generalized congenital weakness. The symptomatic female carriers typically have limb-girdle weakness, asymmetric muscle weakness and skeletal size, urinary incontinence, facial weakness, ptosis and ophthalmoplegia. Here we describe a Finnish family with two females with lower limb spasticity and hyperreflexia resembling spastic paraplegia, gait difficulties and asymmetric muscle weakness in the limbs. A whole exome sequencing identified a heterozygous pathogenic missense variant MTM1 c.1262G > A, p.(Arg421Gln) segregating in the family. The variant has previously been detected in male and female patients with XLMTM. Muscle biopsy of one of the females showed variation in the myofiber diameter, atrophic myofibers, central nuclei and necklace fibers consistent with a diagnosis of XLMTM. This report suggests association between spastic paraplegia and pathogenic MTM1 variants expanding the phenotypic spectrum potentially associated with XLMTM, but the possible association needs to be confirmed by additional cases.

[Hereditary spastic paraplegia type 4 (SPG4) in Russian patients]. / Nasledstvennaia spasticheskaia paraplegiia 4-go tipa u rossiiskikh bol'nykh.

AIM: To investigate molecular, clinical and genealogical characteristics of SPG4 in a first representative Russian group, to estimate SPG4 proportion among all DNA-diagnosed spastic paraplegias. MATERIAL AND METHODS: Fifty unrelated Russian families with SPG4 detected in the course of clinical and molecular studies of spastic paraplegias were studied. Clinical, genealogical and several molecular methods were used, i.e. Sanger sequencing of SPAST, massive parallel sequencing MPS (panel 'hereditary paraplegias') and multiplex ligation-dependent amplification MLPA. RESULTS: SPG4 proportion was 56% among all DNA verified SPG cases (90 families/14 forms) and 68% in subgroup of dominant SPG. In 50 families, 43 different SPAST mutations were detected, of which 21 were novel; percentage of large rearrangements was 30% (13 mutations in 15 families). Four mutations were detected in two families each, nonsense mutation c.1291C>T (p.Arg431*) in 4 unrelated families. Proportion of familial cases was 68%, pedigrees with 'missing' disease in elderly carriers pointed to incomplete penetrance. Age of onset varied from one year to 58 years, middle-age onset was common but the proportion of early-onset cases, particularly in male index cases, was also high. Onset age showed marked intrafamilial differences (more than 10 years in 14 pedigrees, up to 50 year in one) and between families with identical mutations. Insidious onset, slow development with most patients ambulant and 'uncomplicated' phenotype were typical. Cases with additional signs were: a family with ataxia in both patients, two families with epilepsy in one of SPG4 patients; three families with mild mental deficiency in one of SPG4 patients. A case described separately is a 29-year-old male patient with indeterminate myalgia and no SPG signs in whom SPAST previously reported mutation p.Ala430Thr de novo was an unexpected MPS finding. CONCLUSION: SPG4 substantially predomimates in SPG structure in Russian families as practically everywhere else. Half of 43 detected SPAST mutations are novel, the proportion of large rearrangements is 30% higher than in most of studies. Clinical inter- and intrafamilial variability concerns mostly age of onset. SPG4 is not exclusively adult-onset as was thought earlier.

Hereditary spastic paraplegia associated with a rare IFIH1 mutation: a case report and literature review.

Here, the pathogenesis of an IFIH1 gene mutation is discussed through the analysis of a sporadic case of hereditary spastic paraplegia. Next-generation sequencing was performed for the patient and his family members to detect mutations at the IFIH1 locus. The patient and his father were found to carry the same heterozygous missense mutation (c.1093A > G; p.Gly495Arg), while the patient's mother does not carry this mutation. This is the first report of this heterozygous IFIH1 mutation and it is predicted to be disease-causing.

Treatable cause of hereditary spastic paraplegia: eight cases of combined homocysteinaemia with methylmalonic aciduria.

Combined homocysteinemia with methylmalonic aciduria (MMA/HCY) are genetic disorders of intracellular cobalamin (cbl) transport and processing that cause downstream deficiencies in methylcobalamin and adenosylcobalamin. Untreated disease is characterized biochemically by methylmalonic aciduria and hyperhomocysteinemia, while the clinical features are variable. When spastic paraplegia (SP) dominates, it is difficult to differentiate from hereditary spastic paraplegia (HSP). Clinical, biochemical and imaging features were reviewed in eight patients with MMA/HCY that mimicked HSP. Seven males and one female were enrolled. The median onset age was 13 years old (range 7-26 years old). The median time delay of diagnosis was 20.5 months (range 2-60 months). Spastic gait was the first symptom in four patients, while the other four patients presented with chronic emotional abnormalities or cognitive impairment. The main clinical manifestation was SP, and other neurological symptoms included cognitive impairment (5/8), spastic dysuria (3/8), personality change and depression (3/8), ataxia (2/8), seizures (2/8), limb numbness (2/8), and developmental delay (2/8). When patients were diagnosed, the mean serum homocysteine level, the methylmalonic acid level in urine, the serum propionylcarnitine (C3) level and the ratios of C3-to-acetylcarnitine (C2) and free carnitine (C0) were all dramatically elevated. Cranial MRIs showed nothing remarkable except mild brain atrophy. All spinal MRIs were normal except for case 8. Definite compound heterozygous mutations in MMACHC were detected in five cases. Follow-up indicated partial improvement in all the patients after intramuscular cbl, oral betaine and folate, supporting the diagnosis of MMA/HCY. Our data highlight the need for extensive investigation of intracellular cbl transport and processing, when spastic paraparesis is a prominent component of the clinical picture. Testing for urine methylmalonic acid and serum homocysteine levels is a simple but critical approach in suspected cases. Genetic testing, especially for MMACHC gene mutations, is needed. Raising awareness of this disorder could result in the timely initiation of targeted treatment, which may significantly improve patient outcomes.

Hereditary Myelopathies.

PURPOSE OF REVIEW: Hereditary myelopathies are very diverse genetic disorders, and many of them represent a widespread neurodegenerative process rather than isolated spinal cord dysfunction. This article reviews various types of inherited myelopathies, with emphasis on hereditary spastic paraplegias and spastic ataxias. RECENT FINDINGS: The ever-growing number of myelopathy-causing genes and broadening of phenotype-genotype correlations makes the molecular diagnosis of inherited myelopathies a daunting task. This article emphasizes the main phenotypic clusters among inherited myelopathies that can facilitate the diagnostic process. This article focuses on newly identified genetic causes and the most important identifying clinical features that can aid the diagnosis, including the presence of a characteristic age of onset and additional neurologic signs such as leukodystrophy, thin corpus callosum, or amyotrophy. SUMMARY: The exclusion of potentially treatable causes of myelopathy remains the most important diagnostic step. Syndromic diagnosis can be supported by molecular diagnosis, but the genetic diagnosis at present does not change the management. Moreover, a negative genetic test does not exclude the diagnosis of a hereditary myelopathy because comprehensive molecular testing is not yet available, and many disease-causing genes remain unknown.

Gait phenotypes in paediatric hereditary spastic paraplegia revealed by dynamic time warping analysis and random forests.

The Hereditary Spastic Paraplegias (HSP) are a group of heterogeneous disorders with a wide spectrum of underlying neural pathology, and hence HSP patients express a variety of gait abnormalities. Classification of these phenotypes may help in monitoring disease progression and personalizing therapies. This is currently managed by measuring values of some kinematic and spatio-temporal parameters at certain moments during the gait cycle, either in the doctor´s surgery room or after very precise measurements produced by instrumental gait analysis (IGA). These methods, however, do not provide information about the whole structure of the gait cycle. Classification of the similarities among time series of IGA measured values of sagittal joint positions throughout the whole gait cycle can be achieved by hierarchical clustering analysis based on multivariate dynamic time warping (DTW). Random forests can estimate which are the most important isolated parameters to predict the classification revealed by DTW, since clinicians need to refer to them in their daily practice. We acquired time series of pelvic, hip, knee, ankle and forefoot sagittal angular positions from 26 HSP and 33 healthy children with an optokinetic IGA system. DTW revealed six gait patterns with different degrees of impairment of walking speed, cadence and gait cycle distribution and related with patient's age, sex, GMFCS stage, concurrence of polyneuropathy and abnormal visual evoked potentials or corpus callosum. The most important parameters to differentiate patterns were mean pelvic tilt and hip flexion at initial contact. Longer time of support, decreased values of hip extension and increased knee flexion at initial contact can differentiate the mildest, near to normal HSP gait phenotype and the normal healthy one. Increased values of knee flexion at initial contact and delayed peak of knee flexion are important factors to distinguish GMFCS stages I from II-III and concurrence of polyneuropathy.

Toe Walking: A Neurological Perspective After Referral From Pediatric Orthopaedic Surgeons.

BACKGROUND: Toe walking (TW) in children is often idiopathic in origin. Our purpose was to determine the incidence of a neurological etiology for TW in patients seen in the neurology clinic after referral from pediatric orthopaedic surgeons. METHODS: We performed an Institutional Review Board approved retrospective review of 174 patients referred to the neurology clinic from orthopaedic surgeons at an academic pediatric tertiary care center between January 2010 and September 2015. Medical records were reviewed and data recorded including pertinent family history, birth history, age of initial ambulation, physical examination findings, and workup results including neuroimaging, neurophysiological studies, and findings of genetic testing and tissue biopsy. RESULTS: Sixty-two percent (108/174) of patients were found to have a neurological etiology for TW. Final pathologic diagnoses were: 37% (40/108) previously undiagnosed cerebral palsy (CP), 16.7% (18/108) peripheral neuropathy, 15.7% (17/108) autism spectrum disorder, 13.9% (15/108) hereditary spastic paraparesis, 8.3% (9/108) attention deficit hyperactivity disorder, 5.6% (6/108) syndromic diagnosis, and 2.8% (3/108) spinal cord abnormality. Ankle equinus contractures were noted in idiopathic and neurological patients and did not indicate a pathologic origin. Seventy-one percent of unilateral toe walkers and 32% of bilateral but asymmetric toe walkers were diagnosed with CP (P<0.001). Twenty-six percent of 145 brain magnetic resonance imaging studies diagnosed CP. Of the 125 (72%) with spinal imaging, 3 had spinal pathology to account for TW. Fourteen percent of 87 subjects with an electromyography/nerve conduction study had abnormal results indicating a peripheral polyneuropathy. CONCLUSIONS: An underlying pathologic diagnosis was found in 62% of patients referred to neurology for TW. A concerning birth history, delayed initial ambulation, unilateral TW, upper or lower motor neuron signs on examination, or behavioral features may suggest a pathologic diagnosis. Ankle contracture is not predictive of an abnormal diagnosis and can be found in idiopathic patients. CP, peripheral neuropathy, autism spectrum disorder, and hereditary spastic paraparesis are the most common pathologic diagnoses identified in our population. LEVEL OF EVIDENCE: Level III-retrospective cohort.

Severe 5,10-methylenetetrahydrofolate reductase deficiency: a rare, treatable cause of complicated hereditary spastic paraplegia.

BACKGROUND AND PURPOSE: Juvenile- or adult-onset forms of severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency manifesting as complicated hereditary spastic paraplegia have rarely been described. METHODS: Two siblings with mental retardation developed a progressive spastic paraparesis in their late teens. Their diagnostic assessment included extensive neurophysiologic, neuroimaging and metabolic studies. RESULTS: Brain magnetic resonance imaging showed occipital white matter alterations, and electromyography documented a mixed polyneuropathy. Severe hyperhomocisteinemia (>150 µmol/L) associated with the characteristic amino acid profile suggested a diagnosis of severe MTHFR deficiency, confirmed by MTHFR direct sequencing. Treatment with betaine and vitamins benefitted patients' symptoms and diagnostic features. CONCLUSIONS: Severe MTHFR deficiency can be a rare, treatable cause of autosomal recessive complicated hereditary spastic paraplegia. Its screening should be part of the diagnostic flowchart for these disorders.