A needle in a haystack? The impact of a targeted epilepsy gene panel in the identification of a treatable but rapidly progressive metabolic epilepsy: CLN2 disease.

BACKGROUND: Neuronal ceroid lipofuscinoses (NCL) are a group of autosomal recessive, inherited, lysosomal, and neurodegenerative diseases that causes progressive dementia, seizures, movement disorders, language delay/regression, progressive visual failure, and early death. Neuronal ceroid lipofuscinosis type 2 (CLN2), caused by biallelic pathogenic variants of the TPP1 gene, is the only NCL with an approved targeted therapy. The laboratory diagnosis of CLN2 is established through highly specific tests, leading to diagnostic delays and eventually hampering the provision of specific treatment for patients with CLN2. Epilepsy is a common and clinically-identifiable feature among NCLs, and seizure onset is the main driver for families to seek medical care. OBJECTIVE: To evaluate the results of the Latin America Epilepsy and Genetics Program, an epilepsy gene panel, as a comprehensive tool for the investigation of CLN2 among other genetic causes of epilepsy. METHODS: A total of 1,284 patients with epilepsy without a specific cause who had at least 1 symptom associated with CLN2 were screened for variants in 160 genes associated with epilepsy or metabolic disorders presenting with epilepsy through an epilepsy gene panel. RESULTS: Variants of the TPP1 gene were identified in 25 individuals (1.9%), 21 of them with 2 variants. The 2 most frequently reported variants were p.Arg208* and p.Asp276Val, and 2 novel variants were detected in the present study: p.Leu308Pro and c.89 + 3G > C Intron 2. CONCLUSION: The results suggest that these genetic panels can be very useful tools to confirm or exclude CLN2 diagnosis and, if confirmed, provide disease-specific treatment for the patients.

ANTECEDENTES: As lipofuscinoses ceroides neuronais (neuronal ceroid lipofuscinoses, NCLs, em inglês) são um grupo de doenças autossômicas recessivas, hereditárias, lisossomais e neurodegenerativas que causam demência progressiva, crises epiléticas, distúrbios de movimento, atraso/regressão da linguagem, deficiência visual progressiva e morte precoce. A lipofuscinose ceroide neuronal tipo 2 (neuronal ceroid lipofuscinosis type 2, CLN2, em inglês), causada por variantes patogênicas bialélicas do gene TPP1, é a única com terapia-alvo aprovada. O diagnóstico laboratorial é realizado por testes específicos, o que leva a atrasos diagnósticos e, consequentemente, prejudica a disponibilização de tratamento. A epilepsia é uma característica comum e clinicamente identificável entre as NCLs, e o início das convulsões é o principal motivo para as famílias buscarem atendimento médico. OBJETIVO: Avaliar os resultados do Programa de Epilepsia e Genética da América Latina, um painel genético, como uma ferramenta abrangente para a investigação de CLN2 entre outras causas genéticas de epilepsia. MéTODOS: Um total de 1.284 pacientes com epilepsia sem uma causa específica e que tinham pelo menos 1 sintoma associado à CLN2 foram rastreados em busca de variantes em 160 genes associados à epilepsia ou a distúrbios metabólicos que apresentam epilepsia, por meio de um painel genético. RESULTADOS: Variantes do gene TPP1 foram identificadas em 25 indivíduos (1,9%), sendo que ; 21 apresentavam duas variantes. As duas variantes mais frequentes foram p.Arg208* e p.Asp276Val, e duas variantes novas foram detectadas neste: p.Leu308Pro e c.89 + 3G > C Intron 2. CONCLUSãO: Os resultados sugerem que os painéis genéticos de epilepsia podem ser uma ferramenta útil para confirmar ou excluir o diagnóstico de CLN2 e, se confirmado, fornecer tratamento específico para os pacientes.

Disease progression in Sanfilippo type B: Case series of Brazilian patients.

Mucopolysaccharidosis type IIIB (MPS IIIB) is caused by deficiency of alpha-N-acetylglucosaminidase, leading to storage of heparan sulphate. The disease is characterized by intellectual disability and hyperactivity, among other neurological and somatic features. Here we studied retrospective data from a total of 19 MPS IIIB patients from Brazil, aiming to evaluate disease progression. Mean age at diagnosis was 7.2 years. Speech delay was one of the first symptoms to be identified, around 2-3 years of age. Behavioral alterations include hyperactivity and aggressiveness, starting around age four. By the end of the first decade, patients lost acquired abilities such as speech and ability to walk. Furthermore, as disease progresses, respiratory, cardiovascular and joint abnormalities were found in more than 50% of the patients, along with organomegaly. Most common cause of death was respiratory problems. The disease progression was characterized in multiple systems, and hopefully these data will help the design of appropriate clinical trials and clinical management guidelines.

Mono-allelic KCNB2 variants lead to a neurodevelopmental syndrome caused by altered channel inactivation.

Ion channels mediate voltage fluxes or action potentials that are central to the functioning of excitable cells such as neurons. The KCNB family of voltage-gated potassium channels (Kv) consists of two members (KCNB1 and KCNB2) encoded by KCNB1 and KCNB2, respectively. These channels are major contributors to delayed rectifier potassium currents arising from the neuronal soma which modulate overall excitability of neurons. In this study, we identified several mono-allelic pathogenic missense variants in KCNB2, in individuals with a neurodevelopmental syndrome with epilepsy and autism in some individuals. Recurrent dysmorphisms included a broad forehead, synophrys, and digital anomalies. Additionally, we selected three variants where genetic transmission has not been assessed, from two epilepsy studies, for inclusion in our experiments. We characterized channel properties of these variants by expressing them in oocytes of Xenopus laevis and conducting cut-open oocyte voltage clamp electrophysiology. Our datasets indicate no significant change in absolute conductance and conductance-voltage relationships of most disease variants as compared to wild type (WT), when expressed either alone or co-expressed with WT-KCNB2. However, variants c.1141A>G (p.Thr381Ala) and c.641C>T (p.Thr214Met) show complete abrogation of currents when expressed alone with the former exhibiting a left shift in activation midpoint when expressed alone or with WT-KCNB2. The variants we studied, nevertheless, show collective features of increased inactivation shifted to hyperpolarized potentials. We suggest that the effects of the variants on channel inactivation result in hyper-excitability of neurons, which contributes to disease manifestations.

Further delineation of the rare GDACCF (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies syndrome): genotype and phenotype of 22 patients with ZNF148 mutations.

BACKGROUND: Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far. METHODS: As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals. RESULTS: The core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the ZNF148 gene. Heterozygous deletion including the entire ZNF148 gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families. CONCLUSION: The GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term 'GDACCF syndrome' with 'ZNF148-related neurodevelopmental disorder'.

Leigh Syndrome Spectrum: A Portuguese Population Cohort in an Evolutionary Genetic Era.

Mitochondrial diseases are the most common inherited inborn error of metabolism resulting in deficient ATP generation, due to failure in homeostasis and proper bioenergetics. The most frequent mitochondrial disease manifestation in children is Leigh syndrome (LS), encompassing clinical, neuroradiological, biochemical, and molecular features. It typically affects infants but occurs anytime in life. Considering recent updates, LS clinical presentation has been stretched, and is now named LS spectrum (LSS), including classical LS and Leigh-like presentations. Apart from clinical diagnosis challenges, the molecular characterization also progressed from Sanger techniques to NGS (next-generation sequencing), encompassing analysis of nuclear (nDNA) and mitochondrial DNA (mtDNA). This upgrade resumed steps and favored diagnosis. Hereby, our paper presents molecular and clinical data on a Portuguese cohort of 40 positive cases of LSS. A total of 28 patients presented mutation in mtDNA and 12 in nDNA, with novel mutations identified in a heterogeneous group of genes. The present results contribute to the better knowledge of the molecular basis of LS and expand the clinical spectrum associated with this syndrome.

Biallelic structural variations within FGF12 detected by long-read sequencing in epilepsy.

We discovered biallelic intragenic structural variations (SVs) in FGF12 by applying long-read whole genome sequencing to an exome-negative patient with developmental and epileptic encephalopathy (DEE). We also found another DEE patient carrying a biallelic (homozygous) single-nucleotide variant (SNV) in FGF12 that was detected by exome sequencing. FGF12 heterozygous recurrent missense variants with gain-of-function or heterozygous entire duplication of FGF12 are known causes of epilepsy, but biallelic SNVs/SVs have never been described. FGF12 encodes intracellular proteins interacting with the C-terminal domain of the alpha subunit of voltage-gated sodium channels 1.2, 1.5, and 1.6, promoting excitability by delaying fast inactivation of the channels. To validate the molecular pathomechanisms of these biallelic FGF12 SVs/SNV, highly sensitive gene expression analyses using lymphoblastoid cells from the patient with biallelic SVs, structural considerations, and Drosophila in vivo functional analysis of the SNV were performed, confirming loss-of-function. Our study highlights the importance of small SVs in Mendelian disorders, which may be overlooked by exome sequencing but can be detected efficiently by long-read whole genome sequencing, providing new insights into the pathomechanisms of human diseases.

A recurrent homozygous LMNA missense variant p.Thr528Met causes atypical progeroid syndrome characterized by mandibuloacral dysostosis, severe muscular dystrophy, and skeletal deformities.

Atypical progeroid syndromes (APS) are premature aging syndromes caused by pathogenic LMNA missense variants, associated with unaltered expression levels of lamins A and C, without accumulation of wild-type or deleted prelamin A isoforms, as observed in Hutchinson-Gilford progeria syndrome (HGPS) or HGPS-like syndromes. A specific LMNA missense variant, (p.Thr528Met), was previously identified in a compound heterozygous state in patients affected by APS and severe familial partial lipodystrophy, whereas heterozygosity was recently identified in patients affected by Type 2 familial partial lipodystrophy. Here, we report four unrelated boys harboring homozygosity for the p.Thr528Met, variant who presented with strikingly homogeneous APS clinical features, including osteolysis of mandibles, distal clavicles and phalanges, congenital muscular dystrophy with elevated creatine kinase levels, and major skeletal deformities. Immunofluorescence analyses of patient-derived primary fibroblasts showed a high percentage of dysmorphic nuclei with nuclear blebs and typical honeycomb patterns devoid of lamin B1. Interestingly, in some protrusions emerin or LAP2α formed aberrant aggregates, suggesting pathophysiology-associated clues. These four cases further confirm that a specific LMNA variant can lead to the development of strikingly homogeneous clinical phenotypes, in these particular cases a premature aging phenotype with major musculoskeletal involvement linked to the homozygous p.Thr528Met variant.

Corrigendum to " Biochemical diagnosis of aromatic-L-amino acid decarboxylase deficiency (AADCD) by assay of AADC activity in plasma using liquid chromatography/tandem mass spectrometry" [32/100888 (2022) page 1-4].

[This corrects the article DOI: 10.1016/j.ymgmr.2022.100888.].

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.

Quantification of lysosphingomyelin and lysosphingomyelin-509 for the screening of acid sphingomyelinase deficiency.

BACKGROUND: Acid sphingomyelinase deficiency (ASMD) is a lysosomal disorder caused by deficiency of acid sphingomyelinase (ASM) leading to the accumulation of sphingomyelin (SM) in a variety of cell types. Lysosphingomyelin (LysoSM) is the de-acetylated form of SM and it has been shown as a biomarker for ASMD in tissues, plasma, and dried blood spots (DBS) and lysosphingomyelin-509 (LysoSM509) is the carboxylated analogue of LysoSM. High levels of Lysosphingomyelin 509 (LysoSM509) have also been shown in ASMD patients. In this study, we report the utility of the quantification of LysoSM and LysoSM509 in DBS of patients from Latin America with ASMD by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). RESULTS: DBS samples from 14 ASMD patients were compared with 15 controls, and 44 general newborns. All patients had their diagnosis confirmed by the quantification of ASM and the measurement of the activity of chitotriosidase. All patients had significantly higher levels of lysoSM and lysoSM509 compared to controls and general newborns. CONCLUSIONS: The quantification of lysosphingolipids in DBS is a valuable tool for the diagnosis of ASMD patients and lysoSM can be useful in the differential diagnosis with NPC. This method is also valuable in the ASMD newborn screening process.

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.

Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation.

PURPOSE: To summarise the clinical, molecular and biochemical phenotype of mannosyl-oligosaccharide glucosidase-related congenital disorders of glycosylation (MOGS-CDG), which presents with variable clinical manifestations, and to analyse which clinical biochemical assay consistently supports diagnosis in individuals with bi-allelic variants in MOGS. METHODS: Phenotypic characterisation was performed through an international and multicentre collaboration. Genetic testing was done by exome sequencing and targeted arrays. Biochemical assays on serum and urine were performed to delineate the biochemical signature of MOGS-CDG. RESULTS: Clinical phenotyping revealed heterogeneity in MOGS-CDG, including neurological, immunological and skeletal phenotypes. Bi-allelic variants in MOGS were identified in 12 individuals from 11 families. The severity in each organ system was variable, without definite genotype correlation. Urine oligosaccharide analysis was consistently abnormal for all affected probands, whereas other biochemical analyses such as serum transferrin analysis was not consistently abnormal. CONCLUSION: The clinical phenotype of MOGS-CDG includes multisystemic involvement with variable severity. Molecular analysis, combined with biochemical testing, is important for diagnosis. In MOGS-CDG, urine oligosaccharide analysis via matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry can be used as a reliable biochemical test for screening and confirmation of disease.

Biochemical diagnosis of aromatic-L-amino acid decarboxylase deficiency (AADCD) by assay of AADC activity in plasma using liquid chromatography/tandem mass spectrometry.

Aromatic l-amino acid decarboxylase (AADC, EC 4.1.1.28) deficiency is a rare genetic disorder characterized by developmental delay, oculogyric crises, autonomic dysfunction and other problems, caused by biallelic mutations in the DDC gene leading to deficient activity of aromatic l-amino acid decarboxylase, an enzyme involved in the formation of important neurotransmitters, such as dopamine and serotonin. A clinical development program of gene therapy for AADC deficiency is ongoing. An important step for the success of this therapy is the early and precise identification of the affected individuals, but it has been estimated that around 90% of the cases remain undiagnosed. The availability measurement of the AADC activity is mandatory for an accurate biochemical diagnosis. Based on these statements, our objectives were to develop a liquid chromatography tandem mass spectrometry (LC-MS/MS) method suitable for the determination of the AADC activity, and to evaluate its capacity to confirm the deficiency of AADC in potential patients in Brazil. The AADC activities were measured in plasma samples of seven AADC deficient patients and 35 healthy controls, after enzymatic reaction and LC-MS/MS analysis of dopamine, the main reaction product. The results obtained showed clear discrimination between confirmed AADC deficient patients and healthy controls. The method presented here could be incorporated in the IEM laboratories for confirmation of the diagnosis of when a suspicion of AADC deficiency is present due to clinical signs and/or abnormal biomarkers, including when an increased level of 3-O-methyldopa (3-OMD) is found in dried blood spots (DBS) samples from high-risk patients or from newborn screening programs.

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)

Fifteen years of enzyme replacement therapy for mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome): a case report.

BACKGROUND: Mucopolysaccharidosis VI, or Maroteaux-Lamy disease, is an autosomal recessive disease characterized by deficiency of the enzyme arylsulfatase B in the lysosomal catabolism of glycosaminoglycans. Due to reduced (or even null) enzyme activity, glycosaminoglycans (mainly dermatan sulfate) accumulates, leading to a multisystemic disease. Mucopolysaccharidosis VI induces reduced growth, coarse face, audiovisual deficits, osteoarticular deformities, and cardiorespiratory issues, hampering the quality of life of the patient. Enzyme replacement therapy with galsulfase (Naglazyme, BioMarin Pharmaceuticals Inc., USA) is the specific treatment for this condition. Although studies have shown that enzyme replacement therapy slows the progression of the disease, the effects of long-term enzyme replacement therapy remain poorly understood. CASE PRESENTATION: A 29-year-old, Caucasian, male patient diagnosed with mucopolysaccharidosis VI was treated with enzyme replacement therapy for over 15 years. Enzyme replacement therapy was initiated when patient was 13 years old. The patient evolved multiplex dysostosis, carpal tunnel syndrome, thickened mitral valve, and hearing and visual loss. CONCLUSIONS: Although enzyme replacement therapy did not prevent the main signs of mucopolysaccharidosis VI, it slowed their progression. Additionally, enzyme replacement therapy was associated with a longer survival compared with the untreated affected sibling. Taken together, the results indicate that enzyme replacement therapy positively modified the course of the disease.

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)

Sanfilippo syndrome type B: Analysis of patients diagnosed by the MPS Brazil Network.

Mucopolysaccharidosis type IIIB is a rare autosomal recessive disorder characterized by deficiency of the enzyme N-acetyl-alpha-d-glucosaminidase (NAGLU), caused by biallelic pathogenic variants in the NAGLU gene, which leads to storage of heparan sulfate and a series of clinical consequences which hallmark is neurodegeneration. In this study clinical, epidemiological, and biochemical data were obtained from MPS IIIB patients diagnosed from 2004-2019 by the MPS Brazil Network ("Rede MPS Brasil"), which was created with the goal to provide an easily accessible and comprehensive investigation of all MPS types. One hundred and ten MPS IIIB patients were diagnosed during this period. Mean age at diagnosis was 10.9 years. Patients were from all over Brazil, with a few from abroad, with a possible cluster of MPS IIIB identified in Ecuador. All patients had increased urinary levels of glycosaminoglycans and low NAGLU activity in blood. Main clinical symptoms reported at diagnosis were coarse facies and neurocognitive regression. The most common variant was p.Leu496Pro (30% of alleles). MPS IIIB seems to be relatively frequent in Brazil, but patients are diagnosed later than in other countries, and reasons for that probably include the limited awareness about the disease by health professionals and the difficulties to access diagnostic tests, factors that the MPS Brazil Network is trying to mitigate.

Corrigendum to "Evaluation of 3-O-methyldopa as a biomarker for aromatic L-amino acid decarboxylase deficiency in 7 Brazilian cases" [27/100744/2021/ pages: 1-4].

[This corrects the article DOI: 10.1016/j.ymgmr.2021.100744.].