Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association.

ATP6AP1-CDG is an X-linked disorder typically characterized by hepatopathy, immunodeficiency, and an abnormal type II transferrin glycosylation pattern. Here, we present 11 new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1-CDG to include dystonia, hepatocellular carcinoma, and lysosomal abnormalities on hepatic histology. Three of our subjects received successful liver transplantation. We performed N-glycan profiling of total and fractionated plasma proteins for six patients and show associations with varying phenotypes, demonstrating potential diagnostic and prognostic value of fractionated N-glycan profiles. The aberrant N-linked glycosylation in purified transferrin and remaining plasma glycoprotein fractions normalized in one patient post hepatic transplant, while the increases of Man4GlcNAc2 and Man5GlcNAc2 in purified immunoglobulins persisted. Interestingly, in the single patient with isolated immune deficiency phenotype, elevated high-mannose glycans were detected on purified immunoglobulins without glycosylation abnormalities on transferrin or the remaining plasma glycoprotein fractions. Given the diverse and often tissue specific clinical presentations and the need of clinical management post hepatic transplant in ATP6AP1-CDG patients, these results demonstrate that fractionated plasma N-glycan profiling could be a valuable tool in diagnosis and disease monitoring.

Achondroplasia in Latin America: practical recommendations for the multidisciplinary care of pediatric patients.

BACKGROUND: Achondroplasia is the most common bone dysplasia associated with disproportionate short stature, and other comorbidities, such as foramen magnum stenosis, thoracolumbar kyphosis, lumbar hyperlordosis, genu varum and spinal compression. Additionally, patients affected with this condition have higher frequency of sleep disorders, ear infections, hearing loss and slowed development milestones. Considering these clinical features, we aimed to summarize the regional experts' recommendations for the multidisciplinary management of patients with achondroplasia in Latin America, a vast geographic territory with multicultural characteristics and with socio-economical differences of developing countries. METHODS: Latin American experts (from Argentina, Brazil, Chile and Colombia) particiáted of an Advisory Board meeting (October 2019), and had a structured discussion how patients with achondroplasia are followed in their healthcare centers and punctuated gaps and opportunities for regional improvement in the management of achondroplasia. RESULTS: Practical recommendations have been established for genetic counselling, prenatal diagnosis and planning of delivery in patients with achondroplasia. An outline of strategies was added as follow-up guidelines to specialists according to patient developmental phases, amongst them neurologic, orthopedic, otorhinolaryngologic, nutritional and anthropometric aspects, and related to development milestones. Additionally, the role of physical therapy, physical activity, phonoaudiology and other care related to the quality of life of patients and their families were discussed. Preoperative recommendations to patients with achondroplasia were also included. CONCLUSIONS: This study summarized the main expert recommendations for the health care professionals management of achondroplasia in Latin America, reinforcing that achondroplasia-associated comorbidities are not limited to orthopedic concerns.

Diagnostic challenges in hypophosphatasia in adult patients / Desafios do diagnóstico da hipofosfatasia em adultos

Introdução: Hipofosfatasia é um distúrbio metabólico que afeta a mineralização óssea e dentária, causada por mutações no gene ALPL, levando à deficiência enzimática da fosfatase alcalina tecido não-específica. A forma adulta caracteriza-se por fraturas atípicas do fêmur, osteomalácia, osteoporose, grave osteoartropatia, condrocalcinose e artralgia. Objetivo: Demonstrar desafios diagnósticos relacionados à hipofosfatasia através do relato de dois casos. Paciente 1: feminino, 59 anos, encaminhada para avaliação clínica devido às fraturas patológicas de difícil consolidação e osteoporose generalizada de causa genética. Relata perda dentária precoce da arcada superior, fraturas na coluna, em ombro esquerdo e no fêmur. Atualmente, queixa-se de dor crônica intensa, com uso de múltiplos medicamentos. Achados clínicos, laboratoriais e radiológicos foram compatíveis com o diagnóstico de hipofosfatasia. Paciente 2: masculino, 31 anos, filho da paciente 1, encaminhado para avaliação clínica por fratura patológica precoce em fêmur esquerdo e osteoporose não esclarecida. Atualmente relata dor e claudicação importante em membro inferior esquerdo, associado à lombalgia crônica. Confirmação do diagnóstico de hipofosfatasia por exames laboratoriais e radiológicos e sequenciamento do gene ALPL, aliados ao diagnóstico da sua genitora. Discussão: Hipofosfatasia é uma doença rara de herança autossômica dominante e recessiva. Pacientes acometidos apresentam fraturas constantes, densidade mineral óssea baixa, cicatrização óssea deficitária. É comum a hipofosfatasia ser diagnosticada erroneamente como osteopenia e/ou osteoporose primária, acarretando prejuízos ao paciente. Ressalta-se a importância da história clínica completa e dos antecedentes familiares a fim de se obter um diagnóstico precoce, garantindo, por sua vez, o adequado acompanhamento e manejo terapêutico (AU)

Introduction: hypophosphatasia is a metabolic disorder affecting bone and tooth mineralization, caused by mutations in the ALPL gene leading to enzymatic deficiency of tissue non-specific alkaline phosphatase. The adult form is characterized by atypical femur fractures, osteomalacia, osteoporosis, severe osteoarthropathy, chondrocalcinosis, and arthralgia. Objective: to demonstrate diagnostic challenges related to hypophosphatasia through the report of two cases. Patient 1: female, 59 years old, referred for clinical evaluation due to pathological fractures of difficult consolidation and generalized osteoporosis of genetic cause. She reports early tooth loss in the upper arch, fractures in the spine, left shoulder and femur. Currently, he complains of severe chronic pain, with use of multiple medications. Clinical, laboratory, and radiological findings were compatible with the diagnosis of hypophosphatasia. Patient 2:male, 31 years old, son of patient 1, referred for clinical evaluation due to an early pathological fracture in the left femur and unclear osteoporosis. He currently reports pain and significant claudication in the left lower limb, associated with chronic low back pain. Confirmation of the diagnosis of hypophasatasia by laboratory and radiological tests and sequencing of the ALPL gene combined with the diagnosis of his mother. Discussion: hypophosphatasia is a rare disease of autosomal dominant and recessive inheritance. Affected patients have constant fractures, low bone mineral density, and impaired bone healing. It is common for hypophosphatasia to be misdiagnosed as osteopenia and/or primary osteoporosis, which can be harmful to the patient. The importance of a complete clinical history and family history is emphasized in order to obtain an early diagnosis, ensuring adequate follow-up and therapeutic management (AU)

Desafios do diagnóstico da hipofosfatasia em adultos / Diagnostic challenges in hypophosphatasia in adult patients

RESUMO:Introdução: Hipofosfatasia é um distúrbio metabólico que afeta a mineralização óssea e dentária, causada por mutações no gene ALPL, levando à deficiência enzimática da fosfatase alcalina tecido não-específica. A forma adulta caracteriza-se por fraturas atípicas do fêmur, osteomalácia, osteoporose, grave osteoartropatia, condrocalcinose e artralgia. Objetivo: Demonstrar desafios diagnósticos relacionados à hipofosfatasia através do relato de dois casos. Paciente 1: feminino, 59 anos, encaminhada para avaliação clínica devido às fraturas patológicas de difícil consolidação e osteoporose generalizada de causa genética. Relata perda dentária precoce da arcada superior, fraturas na coluna, em ombro esquerdo e no fêmur. Atualmente, queixa-se de dor crônica intensa, com uso de múltiplos medicamentos. Achados clínicos, laboratoriais e radiológicos foram compatíveis com o diagnóstico de hipofosfatasia. Paciente 2: masculino, 31 anos, filho da paciente 1, encaminhado para avaliação clínica por fratura patológica precoce em fêmur esquerdo e osteoporose não esclarecida. Atualmente relata dor e claudicação importante em membro inferior esquerdo, associado à lombalgia crônica. Confirmação do diagnóstico de hipofosfatasia por exames laboratoriais e radiológicos e sequenciamento do gene ALPL, aliados ao diagnóstico da sua genitora. Discussão: Hipofosfatasia é uma doença rara de herança autossômica dominante e recessiva. Pacientes acometidos apresentam fraturas constantes, densidade mineral óssea baixa, cicatrização óssea deficitária. É comum a hipofosfatasia ser diagnosticada erroneamente como osteopenia e/ou osteoporose primária, acarretando prejuízos ao paciente. Ressalta-se a importância da história clínica completa e dos antecedentes familiares a fim de se obter um diagnóstico precoce, garantindo, por sua vez, o adequado acompanhamento e manejo terapêutico. (AU)

ABSTRACT: Introduction: hypophosphatasia is a metabolic disorder affecting bone and tooth mineralization, caused by mutations in the ALPL gene leading to enzymatic deficiency of tissue non-specific alkaline phosphatase. The adult form is characterized by atypical femur fractures, osteomalacia, osteoporosis, severe osteoarthropathy, chondrocalcinosis, and arthralgia. Objective: to demonstrate diagnostic challenges related to hypophosphatasia through the report of two cases. Patient 1: female, 59 years old, referred for clinical evaluation due to pathological fractures of difficult consolidation and generalized osteoporosis of genetic cause. She reports early tooth loss in the upper arch, fractures in the spine, left shoulder and femur. Currently, he complains of severe chronic pain, with use of multiple medications. Clinical, laboratory, and radiological findings were compatible with the diagnosis of hypophosphatasia. Patient 2:male, 31 years old, son of patient 1, referred for clinical evaluation due to an early pathological fracture in the left femur and unclear osteoporosis. He currently reports pain and significant claudication in the left lower limb, associated with chronic low back pain. Confirmation of the diagnosis of hypophasatasia by laboratory and radiological tests and sequencing of the ALPL gene combined with the diagnosis of his mother. Discussion: hypophosphatasia is a rare disease of autosomal dominant and recessive inheritance. Affected patients have constant fractures, low bone mineral density, and impaired bone healing. It is common for hypophosphatasia to be misdiagnosed as osteopenia and/or primary osteoporosis, which can be harmful to the patient. The importance of a complete clinical history and family history is emphasized in order to obtain an early diagnosis, ensuring adequate follow-up and therapeutic management. (AU)

Doença de Krabbe: relato de casos sobre o espectro fenotípico de uma leucodistrofia metabólica multifacetada

Resumo Introdução: A doença de Krabbe, também conhecida como leucodistrofia de células globoides, é uma enfermidade autossômica recessiva rara causada pela deficiência da galactocerebrosidase (GALC). Seu diagnóstico baseia-se em teste enzimático seguido por estudo genético-molecular do gene GALC. As manifestações clínicas são diversas e incluem alterações motoras, envolvimento cognitivo com irritabilidade, espasticidade e regressão do desenvolvimento, com óbito em idade bastante precoce na forma infantil clássica. Nas formas de início tardio, os fenótipos são mais atenuados com anormalidades da marcha e progressão mais lenta. Objetivos: Demonstrar a variabilidade fenotípica de uma coorte brasileira considerando o caráter multiétnico dessa população e enfatizar a importância do diagnóstico precoce para possível tratamento; uma vez que há evidências de melhora da sua evolução e prognóstico. Relato de Casos: São apresentados três casos de pacientes do sexo masculino com Leucodistrofia de Células Globoides; todos filhos de pais não consanguíneos, com diagnóstico molecular e sem variação comum, reforçando o caráter multiétnico da população brasileira. A idade de início das manifestações clínicas foi variável (um mês, oito meses e dois anos) e o diagnóstico da doença foi realizado entre os três meses e os dois anos de vida. Os pacientes apresentaram atraso no desenvolvimento neuropsicomotor, diversas manifestações neurológicas e a ressonância magnética de encéfalo foi similar entre eles. Os pacientes do estudo não receberam o tratamento, pois não foram diagnosticados precocemente; dois deles apresentaram complicações da doença e evoluíram a óbito. Conclusão: A Leucodistrofia de Células Globoides apresenta uma alta variabilidade fenotípica com múltiplas manifestações. Além disso, o diagnóstico precoce da doença é um desafio que impacta diretamente no prognóstico e na única terapia disponível no momento; o transplante de medula óssea. Adicionalmente, o diagnóstico acurado da enfermidade viabiliza o aconselhamento genético familiar e auxilia na melhora dos cuidados de reabilitação do paciente.

Morquio-like dysostosis multiplex presenting with neuronopathic features is a distinct GLB1-related phenotype.

BACKGROUND: Morquio B disease (MBD) is a distinct GLB1-related dysostosis multiplex presenting a mild phenocopy of GALNS-related Morquio A disease. Previously reported cases from European countries carry the W273L variant on at least one GLB1 allele and exhibit a pure skeletal phenotype (pure MBD). Only a minority of MBD cases have been described with additional neuronopathic findings (MBD plus). OBJECTIVES AND METHODS: With the aim to further describe patterns of MBD-related dysostosis multiplex, we analyzed clinical, biochemical, and genetic features in 17 cases with GLB1-related dysostosis multiplex living and diagnosed in Brazil. RESULTS: About 14 of the 17 individuals had three or more skeletal findings characteristic of Morquio syndrome. Two had no additional neuronopathic features (pure MBD) and 12 exhibited additional neuronopathic features (MBD plus). Three of the 17 cases had mild dysostosis without distinct features of MBD. Seven of the 12 MBD plus patients had signs of spinal cord compression (SCC), as a result of progressive spinal vertebral dysostosis. There was an age-dependent increase in the number of skeletal findings and in the severity of growth impairment. GLB1 mutation analysis was completed in 10 of the 14 MBD patients. T500A occurred in compound heterozygosity in 8 of the 19 alleles. CONCLUSION: Our study extends the phenotypic spectrum of GLB1-related conditions by describing a cohort of patients with MBD and GM1-gangliosidosis (MBD plus). Targeting the progressive nature of the skeletal manifestations in the development of new therapies for GLB1-related conditions is warranted.

Paraparesia espástica complicada como fenótipo neurológico em OPA1 / Complex spastic paraplegia as a neurological phenotype in an opa1 patient

RESUMO: A atrofia óptica autossômica dominante (ADOA) é uma das formas mais comuns de atrofias ópticas hereditárias, e causada por mutações no gene OPA1. Os pacientes afetados por essa doença geralmente apresentam perda visual na primeira década de vida, podendo apresentar manifestações extraoftalmológicas no decorrer dos anos, configurando uma síndrome chamada OPA1 plus ou ADOA-plus. Objetivos: Relatar caso de paciente portadora da síndrome ADOA-plus, estabelecendo correlações com casos descritos na literatura. Relato de caso: Paciente feminino, 30 anos, foi encaminhada para avaliação de quadro de atrofia óptica progressiva associada a sintomas de neuropatia periférica. Aos dois anos, foi diagnosticada com perda visual parcial em consulta de puericultura. Não relatou outros sintomas associados durante a infância e a adolescência. Aos 20 anos, apresentou dificuldades de deambular, fraqueza em membros inferiores e falta de equilíbrio. Aos 25 anos, após extensa investigação, foi identificada, através de sequenciamento de exoma, mutação patológica no gene OPA1 confirmando o diagnóstico ADOA-plus e iniciado tratamento com Coenzima Q10. Atualmente a paciente relata ataxia sensitiva, diminuição da acuidade visual progressiva, fasciculações e câimbras em MMII, disfagia e dispneia. Discussão: Muitos pacientes com ADOA-plus apresentam surdez neurossensorial como sintoma extraoftalmológico mais comum, além de quadros de parkinsonismo e demência, ataxia e ptose. Paciente relatada constitui um caso de atrofia óptica associado à neuropatia periférica, ataxia e miopatia. Devido à ampla variabilidade clínica dessa doença, deve-se investigar mutações no OPA1 em casos de paraparesia espástica progressiva associada à atrofia óptica, visto que possibilidade de tratamento com Coenzima Q10. (AU)

ABSTRACT: Introduction: Autosomal dominant optic atrophy (ADOA) is one of the most common forms of inherited optic atrophies and is caused by mutations in the OPA1 gene. Patients affected by this disease usually present visual loss in the first decade of life, and may present extra-ophthalmologic manifestations over the years, configuring a syndrome called OPA1 plus or ADOA-plus. Objectives: to report the case of a patient with ADOA-plus syndrome, establishing correlations with cases described in the literature, Case report: a 30-year-old female patient was referred for evaluation of progressive optic atrophy associated with symptoms of peripheral neuropathy. At two years of age, she was diagnosed with partial visual loss during a childcare visit. She reported no other associated symptoms during childhood and adolescence. At the age of 20, she presented with difficulty walking, lower limb weakness, and poor balance. At 25, after extensive investigation, a pathological mutation in the OPA1 gene was identified through exome sequencing, confirming the diagnosis of ADOA-plus, and treatment with Coenzyme Q10 was initiated. Currently the patient reports sensory ataxia, progressive decrease in visual acuity, fasciculations and cramps in the lower limbs, dysphagia and dyspnea. Discussion: Many patients with ADOA-plus present sensorineural deafness as the most common extra-ophthalmologic symptom, in addition to parkinsonism and dementia, ataxia and ptosis. The patient reported is a case of optic atrophy associated with peripheral neuropathy, ataxia and myopathy. Due to the wide clinical variability of this disease, OPA1 mutations should be investigated in cases of progressive spastic paraparesis associated with optic atrophy, since the possibility of treatment with Coenzyme Q10. (AU)

BPAN manifesting with febrile seizures and language delay: a case report from Brazil

Neurodegeneration with brain iron accumulation (NBIA) is a complex group of hereditary progressive neurodegenerative diseases characterized by deposition of iron in the basal ganglia. Twelve genetic forms of this disorder have been identified in previous studies. Though they have different inheritance mechanisms all are usually associated with abnormal brain MRI findings. One of NBIA types is an X-linked disorder known as Beta-propeller Protein Associated Neurodegeneration (BPAN). Herein we describe the case of a 4-year-old girl with 2 episodes of febrile seizures, a brain MRI showing nonspecific hyperintense signal in the dentate nucleus area, and delays in language and communication development. Her diagnosis was made based on a genetic evaluation where exome sequencing revealed a mutation in the position chrX:48.933.022 region of the WDR45 gene. The literature describes different clinical presentations for BPAN, each with a different prognosis, suggesting a wide range of possible symptoms of BPAN, including mild cognitive delay and even epileptic encephalopathy (EE). (AU)

Uso de canabidiol como terapia adjuvante em paciente com síndrome de Zellweger: relato de caso / Cannabidiol as adjuvant therapy in a patient with Zellweger syndrome: a case report

RESUMO: Também denominada síndrome cerebrohepatorenal, a síndrome de Zellweger é uma doença autossômica recessiva rara, pertencente ao espectro de erros inatos do metabolismo que afetam os peroxissomos. São causados principalmente por mutações em qualquer um dos 14 genes PEX diferentes que codificam para proteínas envolvidas na montagem do peroxissoma, sendo a mais comum do PEX1. O quadro clínico geralmente é observado no período neonatal e primeira infância, incluindo alterações faciais, hipotonia profunda e ausência de reflexos neonatais, além de disfagia, disfunção hepática e convulsões. O diagnóstico é feito a partir da clínica e testes bioquímicos e confirmados pela visualização da mutação em um dos 14 genes PEX. Como não há tratamento específico, é feito tratamento sintomático. Nosso paciente masculino de 1 ano e 9 meses apresentou a hipotonia congênita como sintoma marcante, além de crises convulsivas recorrentes logo após o nascimento. Evoluiu com necessidade de gastrostomia e estagnação de marcos neuromotores. O diagnóstico foi confirmado aos seis meses, através da dosagem de ácidos graxos de cadeia longa. Crises convulsivas evoluíram de maneira refratária a diversos anticonvulsivantes e com elevada frequência diária, por isso iniciamos canabidiol (CBD-RSHO GOLD) por via enteral que reduziu significantemente as crises. Não há tratamento definitivo para esta enfermidade, sendo importante tratamento sintomático das crises convulsivas e terapias de reabilitação, nesse caso, o uso de (CBD- RSHO GOLD) provocou uma redução de 92% na frequência de crises diárias do paciente. No entanto, não é possível concluir, ainda, melhoras em outros sinais e sintomas. (AU)

ABSTRACT: Also referred to as "brain-liver-kidney" syndrome, the Zellweger syndrome is a rare autosomal recessive disorder, belonging to the spectrum of inborn errors of metabolism that affect peroxisomes. They are caused mainly by mutations in any of the 14 different PEX genes that code for proteins involved in the assembly of peroxisome, being the most common of PEX1. The clinic is usually observed in the neonatal and early childhood period, including facial changes, deep hypotonia, and absence of neonatal reflexes in childhood, in addition to dysphagia, hepatic dysfunction, and seizures. The diagnosis is made from clinical and biochemical tests and confirmed by the visualization of the mutation in one of the 14 PEX genes. Since there is no specific treatment, symptomatic treatment is done. Our 1-year and 9-month-old male patient presented congenital hypotonia as a striking symptom in addition to recurrent seizures shortly after birth. It evolved with the need for gastrostomy and stagnation of neuromotor frames. The diagnosis was confirmed at six months by the measurement of long-chain fatty acids. Convulsive seizures evolved in a manner that was refractory to several anticonvulsants and with a high daily frequency, so we initiated cannabidiol (CBD-RSHO GOLD) by an enteral route that significantly reduced the seizures. Since there is no avail-able treatment for seizures, in this case, the use of CBD-RSHO GOLD reduced by 92% the daily seizure frequency. However, it is not possible to conclude further improvements in other signs and symptoms. (AU)

Perthes-Like Disease Masquerading Non-Classical MPS

Abstract Mucopolysaccharidoses (MPS) are inborn errors of metabolism caused by deficient lysosomal enzymes, leading to organomegaly, hip osteonecrosis, coarse facial features, bone deformities, joint stiffness, cardiac and pulmonary symptoms (MPS VI) or hypermobility (MPS IVA). Some patients may present with non-classical forms of the disease in which osteoarticular abnormalities are the initial symptoms of non-classical forms. As orthopedists and surgeons are the specialists most frequently consulted before the diagnosis, it is critical that MPS may be considered as a differential diagnosis for patients with bone dysplasia. Experts in Latin America reviewed medical records focusing on disease onset, first symptoms and the follow-up clinical and surgical outcomes of non-classical MPS VI and IVA patients. All patients displayed orthopedic issues, which worsened over time, followed by cardiac and ophthalmological abnormalities. Our findings enlighten the necessity of including non-classical MPS as possible diagnosis for patients who report osteoarticular abnormalities in absence of inflammation.

Sanfilippo Syndrome: The Tale of a Challenging Diagnosis

Abstract Sanfilippo syndrome or mucopolysaccharidosis III (MPS III), includes a group of four autosomal recessive lysosomal storage disorders caused by deficient activity of enzymes involved in the catabolism of heparan sulfate. The four types of MPS III are recognized in accordance with the deficient enzyme, resulting in the accumulation of heparan sulfate with particularly deleterious effects in the central nervous system. The incidence of MPS III remains to be established in Latin American countries. We describe the journey of a patient with MPS IIIB whom, even in the presence of speech delay and deterioration, behavioral problems and motor incoordination, showed unaltered urinary glycosaminoglycans (GAGs) levels. An investigation for MPS was undertaken and enzyme analysis indicated a deficiency of alpha-N-acetylglucosaminidase, leading to the diagnosis of MPS IIIB. With the correct diagnosis, the patient's symptoms could be properly managed, and the parents received appropriate genetic counseling. The present case report reinforces the need of investigating MPS III in patients with language delay and/or regression, neurological impairment and behavioral alterations, even when urinary GAGs are within normal range. A definitive diagnosis ends the diagnostic journey and enables the medical team and family to provide a better care for the child.

Development of a Clinical Algorithm for the Early Diagnosis of Mucopolysaccharidosis III

Abstract Mucopolysaccharidosis III (MPS III) is a rare inherited metabolic disease primarily affecting the central nervous system, leading to developmental and/or speech regression. Early diagnosis of the disease is important to introduce appropriate management measures and to optimize therapeutic outcomes. The diagnosis of MPS III is often significantly delayed due to the rarity of the disease, the more attenuated somatic presentation compared to other MPS types, and the symptom overlap with other developmental disorders. To shorten the time to diagnosis, a list of eight early signs and symptoms was identified through an expert system approach by a global, multidisciplinary working group of 13 specialists with expertise in various aspects of MPS and developmental disorders and three parents of MPS III patients. Coarse facial features and persistent hirsutism or prominent, thick eyebrows were identified as the most important MPS III early signs. The list of eight early MPS III signs and symptoms is the first step towards the development of a clinical algorithm aiming to identify neonates and infants with MPS III before the onset of neurocognitive damage, ultimately shortening the diagnostic journey of MPS III patients.

Obsessive-compulsive disorder in a patient with SCA type 1 / Transtorno obsessivo compulsivo em um paciente com SCA tipo 1

For many years, the cerebellum was thought to be only responsible for balance, movement, planning and execution. Nowadays, it is well accepted that most cerebellar connections are involved in non-motor functions. Herein, we provide a case report in which a 27-year-old Brazilian male, diagnosed with Obsessive-Compulsive Disorder (OCD), has demonstrated cerebellar features that could be connected to Spinocerebellar ataxia type 1 (SCA-1), an autosomal dominant polyglutamine neurodegenerative disorder that had been previously ruled out. Since obsessive compulsive symptoms (OCS) are known to correlate with alterations in the cortico-striato-thalamo-cortical circuitry, we propose a possible association between OCS and SCA onset.

Durante muitos anos, o cerebelo foi considerado responsável exclusivamente pelo controle das funções de equilíbrio, movimento, planejamento e execução. Atualmente, já está consagrada a participação das conexões cerebelares em funções não-motoras. Apresentamos um relato de caso de um paciente de 27 anos de idade, diagnosticado com Transtorno Obsessivo-Compulsivo (TOC). O paciente apresentava sintomas cerebelares compatíveis com o diagnóstico de ataxia espinocerebelar tipo 1 (SCA-1), um distúrbio da poliglutamina, autossômico dominante neurodegenerativo, que havia sido previamente descartado. Como os sintomas obsessivos compulsivos (SOC) são conhecidos por correlacionar-se com alterações nos circuitos cortico-estriato-tálamo-cortical, propomos uma possível associação entre o SOC e o início da SCA.

Clinical findings in Brazilian patients with adult GM1 gangliosidosis.

GM1 gangliosidosis is a lysosomal storage disorder caused by ß-galactosidase deficiency. To date, prospective studies for GM1 gangliosidosis are not available, and only a few have focused on the adult form. This retrospective cross-sectional study focused on clinical findings in Brazilian patients with the adult form of GM1 gangliosidosis collected over 2 years. Ten subjects were included in the study. Eight were males and two females, with median age at diagnosis of 11.5 years (IQR, 4-34 years). Short stature and weight below normal were seen in five out of the six patients with data available. Radiological findings revealed that the most frequent skeletal abnormalities were beaked vertebrae, followed by hip dysplasia, and platyspondyly. Neurological examination revealed that dystonia and swallowing problems were the most frequently reported. None of the patients presented hyperkinesia, truncal hypertonia, Parkinsonism, or spinal cord compression. Clinical evaluation revealed impairment in activities of cognitive/intellectual development and behavioral/psychiatric disorders in all nine subjects with data available. Language/speech impairment (dysarthria) was found in 8/9 patients, fine motor and gross motor impairments were reported in 7/9 and 5/9 patients, respectively. Impairment of cognition and daily life activities were seen in 7/9 individuals. Our findings failed to clearly identify typical early or late alterations presented in GM1 gangliosidosis patients, which confirms that it is a very heterogeneous condition with wide phenotypic variability. This should be taken into account in the evaluation of future therapies for this challenging condition.

Mutations in the translocon-associated protein complex subunit SSR3 cause a novel congenital disorder of glycosylation.

The translocon-associated protein (TRAP) complex facilitates the translocation of proteins across the endoplasmic reticulum membrane and associates with the oligosaccharyl transferase (OST) complex to maintain proper glycosylation of nascent polypeptides. Pathogenic variants in either complex cause a group of rare genetic disorders termed, congenital disorders of glycosylation (CDG). We report an individual who presented with severe intellectual and developmental disabilities and sensorineural deafness with an unsolved type I CDG, and sought to identify the underlying genetic basis. Exome sequencing identified a novel homozygous variant c.278_281delAGGA [p.Glu93Valfs*7] in the signal sequence receptor 3 (SSR3) subunit of the TRAP complex. Biochemical studies in patient fibroblasts showed the variant destabilized the TRAP complex with a complete loss of SSR3 protein and partial loss of SSR1 and SSR4. Importantly, all subunit levels were corrected by expression of wild-type SSR3. Abnormal glycosylation status in fibroblasts was confirmed using two markers proteins, GP130 and ICAM1. Our findings confirm mutations in SSR3 cause a novel CDG. A novel frameshift variant in the translocon associated protein, SSR3, disrupts the stability of the TRAP complex and causes a novel Congenital Disorder of Glycosylation.

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

Clinical, ophthalmological, imaging and genetic features in Brazilian patients with ARSACS.

BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an important form of inherited ataxia with a varied clinical spectrum. Detailed studies of phenotype and genotype are necessary to improve diagnosis and elucidate this disorder pathogenesis. OBJECTIVE AND METHODS: To investigate the clinical phenotype, retinal architecture, neuroimaging features and genetic profile of Brazilian patients with ARSACS, we performed neurological and ophthalmological evaluation in thirteen Brazilian patients with molecularly confirmed ARSACS, and examined their mutation profiles. Optical coherence tomography protocol (OCT) consisted in peripapillary retinal nerve fiber layer (RNFL) measurement and qualitative analysis of perifoveal scans. Neuroimaging protocol accessed the frequency of atrophy in cerebellum, corpus callosum and parietal lobe, brainstem signal abnormalities, and posterior fossa arachnoid cysts. We reviewed the literature to delineate the ARSACS phenotype in the largest series worldwide. RESULTS: All patients had ataxia and spasticity, and 11/13 had peripheral neuropathy. Macular microcysts were present in two patients. Peripapillary striations, dentate appearance of inner retina and papillomacular fold were found in eleven cases. All individuals exhibited thickening of RNFL in OCT. The most frequent radiological signs were cerebellar atrophy (13/13), biparietal atrophy (12/13), and linear pontine hypointensities (13/13). Genetic analysis revealed 14 different SACS variants, of which two are novel. CONCLUSION: Macular microcysts, inner retina dentate appearance and papillomacular fold are novel retinal imaging signs of ARSACS. Ophthalmological and neuroimaging changes are common findings in Brazilian patients. The core clinical features of ARSACS are ataxia, spasticity and peripheral neuropathy with onset predominantly in the first decade of life.

Diagnosis and Management of Classica Homocystinuria in Brazil: A Summary of 72 Late-Diagnosed Patients

Abstract This study described a broad clinical characterization of classical homocystinuria (HCU) in Brazil. This was a cross-sectional, observational study including clinical and biochemical data from 72 patients (60 families) from Brazil (South, n = 13; Southeast, n = 37; Northeast, n = 8; North, n = 1; and Midwest, n = 1). Parental consanguinity was reported in 42% of families. Ocular manifestations were the earliest detected symptom (53% of cases), the main reason for diagnostic suspicion (63% of cases), and the most prevalent manifestation at diagnosis (67% of cases). Pyridoxine responsiveness was observed in 14% of patients. Only 22% of nonresponsive patients on treatment had total homocysteine levels <100 mmol/L. Most commonly used treatment strategies were pyridoxine (93% of patients), folic acid (90%), betaine (74%), vitamin B12 (27%), and low-methionine diet + metabolic formula (17%). Most patients diagnosed with HCU in Brazil are late diagnosed, express a severe phenotype, and poor metabolic control. Milder forms of HCU are likely underrepresented due to underdiagnosis.