A multinational study of acute and long-term outcomes of Type 1 galactosemia patients who carry the S135L (c.404C > T) variant of GALT.

Patients with galactosemia who carry the S135L (c.404C > T) variant of galactose-1-P uridylyltransferase (GALT), documented to encode low-level residual GALT activity, have been under-represented in most prior studies of outcomes in Type 1 galactosemia. What is known about the acute and long-term outcomes of these patients, therefore, is based on very limited data. Here, we present a study comparing acute and long-term outcomes of 12 patients homozygous for S135L, 25 patients compound heterozygous for S135L, and 105 patients homozygous for two GALT-null (G) alleles. This is the largest cohort of S135L patients characterized to date. Acute disease following milk exposure in the newborn period was common among patients in all 3 comparison groups in our study, as were long-term complications in the domains of speech, cognition, and motor outcomes. In contrast, while at least 80% of both GALT-null and S135L compound heterozygous girls and women showed evidence of an adverse ovarian outcome, prevalence was only 25% among S135L homozygotes. Further, all young women in this study with even one copy of S135L achieved spontaneous menarche; this is true for only about 33% of women with classic galactosemia. Overall, we observed that while most long-term outcomes trended milder among groups of patients with even one copy of S135L, many individual patients, either homozygous or compound heterozygous for S135L, nonetheless experienced long-term outcomes that were not mild. This was true despite detection by newborn screening and both early and life-long dietary restriction of galactose. This information should empower more evidence-based counseling for galactosemia patients with S135L.

Cerebrotendinous Xanthomatosis: A practice review of pathophysiology, diagnosis, and treatment.

Cerebrotendinous Xanthomatosis represents a rare and underdiagnosed inherited neurometabolic disorder due to homozygous or compound heterozygous variants involving the CYP27A1 gene. This bile acid metabolism disorder represents a key potentially treatable neurogenetic condition due to the wide spectrum of neurological presentations in which it most commonly occurs. Cerebellar ataxia, peripheral neuropathy, spastic paraparesis, epilepsy, parkinsonism, cognitive decline, intellectual disability, and neuropsychiatric disturbances represent some of the most common neurological signs observed in this condition. Despite representing key features to increase diagnostic index suspicion, multisystemic involvement does not represent an obligatory feature and can also be under evaluated during diagnostic work-up. Chenodeoxycholic acid represents a well-known successful therapy for this inherited metabolic disease, however its unavailability in several contexts, high costs and common use in patients at late stages of disease course limit more favorable neurological outcomes for most individuals. This review article aims to discuss and highlight the most recent and updated knowledge regarding clinical, pathophysiological, neuroimaging, genetic and therapeutic aspects related to Cerebrotendinous Xanthomatosis.

Acute Hepatic Porphyria: Pathophysiological Basis of Neuromuscular Manifestations.

Acute hepatic porphyria represents a rare, underdiagnosed group of inherited metabolic disorders due to hereditary defects of heme group biosynthesis pathway. Most patients have their definite diagnosis after several years of complex and disabling clinical manifestations and commonly after life-threatening acute neurovisceral episodes or severe motor handicap. Many key studies in the last two decades have been performed and led to the discovery of novel possible diagnostic and prognostic biomarkers and to the development of new therapeutic purposes, including small interfering RNA-based therapy, specifically driven to inhibit selectively delta-aminolevulinic acid synthase production and decrease the recurrence number of severe acute presentation for most patients. Several distinct mechanisms have been identified to contribute to the several neuromuscular signs and symptoms. This review article aims to present the current knowledge regarding the main pathophysiological mechanisms involved with the acute and chronic presentation of acute hepatic porphyria and to highlight the relevance of such content for clinical practice and in decision making about therapeutic options.

DRPLA: An unusual disease or an underestimated cause of ataxia in Brazil?

BACKGROUND: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant spinocerebellar ataxia caused by pathological expansion of CAG trinucleotide repeats in the ATN1 gene. Most cases were described in patients from Japanese ancestry who presented with adult-onset progressive cerebellar ataxia associated with cognitive impairment, choreoathetosis and other movement disorders. DRPLA has been rarely described in Brazilian patients. METHODS: We performed a retrospective observational multicentric study including six different Neurology Centers in Brazil. All patients with genetically confirmed diagnosis of DRPLA had their medical records evaluated and clinical, genetic and neuroimaging features were analyzed. RESULTS: We describe of eight Brazilian patients (5 male, 3 female) from four nuclear families with genetically confirmed DRPLA. The most common neurological features included cerebellar ataxia (n = 7), dementia (n = 3), chorea (n = 2), psychiatric disturbances (n = 2), progressive myoclonic epilepsy (n = 2) and severe bulbar signs (n = 1). Progressive myoclonic epilepsy was observed in two juvenile-onset cases before 20-year. A large CAG trinucleotide length was observed in the two juvenile-onset cases and genetic anticipation was observed in all cases. Neuroimaging studies disclosed cerebellar atrophy (n = 6), as well as brainstem and cerebellar atrophy (n = 2) and leukoencephalopathy (n = 1). CONCLUSION: The patients described herein reinforce that clinical features of DRPLA are highly influenced by age of onset, genetic anticipation and CAG repetition lengths. There is a large complex spectrum of neurological features associated with DRPLA, varying from pure cerebellar ataxia to dementia associated with other movement disorders (myoclonus, choreoathetosis). DRPLA is an unusual cause of cerebellar ataxia and neurodegeneration in Brazilian patients.

Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, and fatal neurodegenerative disease due to upper and lower motor neuron involvement with symptoms classically occurring in adulthood with an increasing recognition of juvenile presentations and childhood neurodegenerative disorders caused by genetic variants in genes related to Amyotrophic Lateral Sclerosis. The main objective of this study is detail clinical, radiological, neurophysiological, and genetic findings of a Brazilian cohort of patients with a recent described condition known as Spastic Tetraplegia and Axial Hypotonia (STAHP) due to SOD1 deficiency and compare with other cases described in the literature and discuss whether the clinical picture related to SOD1 protein deficiency is a new entity or may be represent a very early-onset form of Amyotrophic Lateral Sclerosis. METHODS: We conducted a case series report which included retrospective data from five Brazilian patients with SOD1 protein deficiency of a Brazilian reference center for Neuromuscular Disorders. Clinical data were obtained from a review of the medical records and descriptive statistics and variables were summarized using counts and percentages of the total population. RESULTS: All 5 patients presented with a childhood-onset neurodegenerative disorders characterized by spastic tetraplegia with axial hypotonia in all cases, with gestational history showing polyhydramnios in 4/5 and intrauterine growth restriction in 3/5 patients, with most patients initially presenting a normal motor development until the six month of life or during the first year followed by a rapidly progressive motor decline with severe dysphagia and respiratory insufficiency in all patients accompanied by cognitive impairment in 3/5 patients. All patients were homozygous for the c.335dupG (p.Cys112Trpfs*11) mutation in the SOD1 gene with completely decreased enzyme activity. CONCLUSIONS: This case series is the biggest data collection of the new recent clinical entity described as Spastic Tetraplegia and Axial Hypotonia (STAHP) due to SOD1 deficiency.

MR imaging of inherited myopathies: a review and proposal of imaging algorithms.

PURPOSE OF REVIEW: The aims of this review are to discuss the imaging modalities used to assess muscle changes in myopathies, to provide an overview of the inherited myopathies focusing on their patterns of muscle involvement in magnetic resonance imaging (MR), and to propose up-to-date imaging-based diagnostic algorithms that can help in the diagnostic workup. CONCLUSION: Familiarization with the most common and specific patterns of muscular involvement in inherited myopathies is very important for radiologists and neurologists, as imaging plays a significant role in diagnosis and follow-up of these patients. KEY POINTS: • Imaging is an increasingly important tool for diagnosis and follow-up in the setting of inherited myopathies. • Knowledge of the most common imaging patterns of muscle involvement in inherited myopathies is valuable for both radiologists and neurologists. • In this review, we present imaging-based algorithms that can help in the diagnostic workup of myopathies.

Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy.

OBJECTIVE: The aim of the study was to report the proportion of homozygous and compound heterozygous variants in the survival motor neuron 1 (SMN1) gene in a large population of patients with spinal muscular atrophy (SMA) and to correlate the severity of the disease with the presence of specific intragenic variants in SMN1 and with the SMN2 copy number. METHODS: Four hundred fifty Brazilian patients with SMA were included in a retrospective study, and clinical data were analyzed compared with genetic data; the SMN2 copy number was obtained by multiplex ligation-dependent probe amplification and pathogenic variants in SMN1 by next-generation sequencing. RESULTS: Four hundred two patients (89.3%) presented homozygous exon 7-SMN1 deletion, and 48 (10.7%) were compound heterozygous for the common deletion in one allele and a point mutation in the other allele. Recurrent variants in exons 3 and 6 (c.460C>T, c.770_780dup and c.734_735insC) accounted for almost 80% of compound heterozygous patients. Another recurrent pathogenic variant was c.5C>G at exon 1. Patients with c.770_780dup and c.734_735insC had a clinical phenotype correlated with SMN2 copy number, whereas the variants c.460C>T and c.5C>G determined a milder phenotype independently of the SMN2 copies. CONCLUSIONS: Patients with specific pathogenic variants (c.460C>T and c.5C>G) presented a milder phenotype, and the SMN2 copy number did not correlate with disease severity in this group.

NFU1 -Related Disorders as Key Differential Diagnosis of Cavitating Leukoencephalopathy.

Genetic leukoencephalopathies represent an expanding group of inherited disorders associated with involvement of brain white matter. Cystic degeneration has been previously described with some acquired or inherited leukoencephalopathies. We describe a 6-month-old Brazilian boy with a 2-month history of severe and rapidly progressive developmental and psychomotor regression and seizures. Neurological examination showed spastic tetraparesis and lethargy. Neuroimaging showed diffuse and symmetric cavitating cystic leukoencephalopathy. Whole-exome sequencing revealed compound heterozygous mutations in the NFU1 gene, providing definite genetic diagnosis of multiple mitochondrial dysfunction syndrome type 1. We report a rare presentation of early-onset cystic leukoencephalopathy in the context of multiple mitochondrial dysfunction syndrome type 1.

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).

Non-motor and Extracerebellar Features in Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant degenerative disease. Pathological studies have demonstrated not only cerebellar and brainstem atrophy, but substantia nigra, motoneurons, basal ganglia, thalamus, and peripheral nerves involvement. These findings may explain non-motor and extra-cerebellar features in SCA2. We accessed the non-motor symptoms and extra-cerebellar signs in SCA2 patients in order to provide a better understanding on pathophysiological mechanisms and natural history of brain degeneration in the disease. Thirty-three SCA2 patients were evaluated and compared with 26 healthy subjects. We investigated the following variables: sleep disorders, cognitive deficit, olfactory impairment, urinary dysfunction, psychiatric symptoms, cramps, pain, movement disorders, and weight loss. SCA2 had a high frequency of REM sleep behavior disorder (48.48 %, N = 16) as well as excessive daytime sleepiness (42.42 %, N = 14). Chorea was present in 15.15 % (N = 5), dystonia in 27.27 % (N = 9), and parkinsonism in 27.27 % (N = 9). Slow saccadic pursuit was present in 87.87 % (N = 29) and ophtalmoparesis in 78.78 % (N = 26) of patients. Regarding sleep disorders, 18.18 % (N = 6) of patients had restless leg syndrome. Dysphagia was present in 39.39 % (N = 13), weight loss 24.24 % (N = 8), and urinary dysfunction 27.27 % (N = 9). Cramps was present in only 6 % of patients (N = 2). This study highlighted the high frequency of non-motor symptoms and extra-cerebellar signs in SCA2. Our findings demonstrate the widespread of nervous system involvement in SCA2 patients and contribute to better understand the natural history of brain degeneration in this genetic condition.

Clinical and epidemiological profiles of non-traumatic myelopathies.

Non-traumatic myelopathies represent a heterogeneous group of neurological conditions. Few studies report clinical and epidemiological profiles regarding the experience of referral services. Objective To describe clinical characteristics of a non-traumatic myelopathy cohort. Method Epidemiological, clinical, and radiological variables from 166 charts of patients assisted between 2001 and 2012 were compiled. Results The most prevalent diagnosis was subacute combined degeneration (11.4%), followed by cervical spondylotic myelopathy (9.6%), demyelinating disease (9%), tropical spastic paraparesis (8.4%) and hereditary spastic paraparesis (8.4%). Up to 20% of the patients presented non-traumatic myelopathy of undetermined etiology, despite the broad clinical, neuroimaging and laboratorial investigations. Conclusion Regardless an extensive evaluation, many patients with non-traumatic myelopathy of uncertain etiology. Compressive causes and nutritional deficiencies are important etiologies of non-traumatic myelopathies in our population.