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Purpose: The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are engaged in diagnosing and treating these patients. Methods: The Writing Group members were appointed by the Mitochondrial Medicine Society. The panel included members with expertise in several different areas. The panel members utilized a comprehensive review of the literature, surveys, and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Results: Consensus-based recommendations are provided for the diagnosis and treatment of mitochondrial disease. Conclusion: The Delphi process enabled the formation of consensus-based recommendations. We hope that these recommendations will help standardize the evaluation, diagnosis, and care of patients with suspected or demonstrated mitochondrial disease. Genet Med 17 9, 689–701.

The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease.

This commentary provides an overview of the putamen as an established target site for gene therapy in treating aromatic l ‐amino acid decarboxylase (AADC) deficiency and Parkinson’s disease, two debilitating neurological disorders that involve motor dysfunction caused by dopamine deficiencies. The neuroanatomy and the function of the putamen in motor control provide good rationales for targeting this brain structure. Additionally, the efficacy and safety of intraputaminal gene therapy demonstrate that restoration of dopamine synthesis in the putamen by using low doses of adeno‐associated viral vector serotype 2 to deliver the hAADC gene is well tolerated. This restoration leads to sustained improvements in motor and nonmotor symptoms of AADC deficiency and improved uptake and conversion of exogenous l ‐DOPA into dopamine in Parkinson’s patients. Graphical Abstract This Commentary provides an overview of putamen‐targeted gene therapies for treating aromatic l ‐amino acid decarboxylase (AADC) deficiency and Parkinson’s disease.

Background Aromatic ʟ‐amino acid decarboxylase (AADC) deficiency is a rare, severe neurological disorder caused by pathogenic variants in the dopa decarboxylase (DDC) gene, resulting in a combined deficiency of monoamine neurotransmitters. Clinically, patients present with a range of dysfunctions that impact motor, autonomic, and cognitive development. The constellation of symptoms of AADC deficiency varies among patients, and clinical presentation falls across a wide spectrum. However, most patients with AADC deficiency experience significant impairments when compared with children with normal development, irrespective of genotype, phenotype, or disease severity. Further, AADC deficiency is associated with increased mortality. Methods In response to the recent approval of a disease‐modifying gene therapy for AADC deficiency, this review presents considerations for the selection of patients for treatment. Conclusion Suggested clinical criteria to determine whether a patient is a candidate for gene therapy are: (1) genetically and biochemically confirmed AADC deficiency; (2) lack of achievement of gross motor milestones and/or persistence of clinically significant movement disorders; (3) persistent neurocognitive or systemic symptoms secondary to AADC deficiency despite standard medical therapy; and (4) informed parental/guardian decision and consent to treatment.

Background Angelman syndrome (AS) is a neurodevelopmental disorder that is caused by maternal genetic deficiency of a gene that encodes E6-AP ubiquitin-protein ligase (gene symbol UBE3A ) mapping to chromosome 15q11-q13. AS leads to stiff and jerky gait, excess laughter, seizures, and severe intellectual disability. In some parts of the brain, the paternally inherited UBE3A gene is subject to genomic imprinting by the action of the UBE3A -antisense transcript ( UBE3A-ATS ) on the paternally inherited allele. Consequently, only the maternally inherited UBE3A gene is expressed in mature neurons. AS occurs due to deletions of the maternal 15q11 − 13 region, paternal uniparental disomy (UPD), imprinting center defects, mutations in the maternal UBE3A gene, or other unknown genetic malfunctions that result in a silenced maternal UBE3A gene in the specific imprinted regions of the brain. Results A potential treatment strategy for AS is to increase methylation of UBE3A-ATS to promote expression of the paternal UBE3A gene and thus ameliorate the clinical phenotypes of AS. We treated two sets of male identical twins with class I deletions with a 1 year treatment trial of either betaine and folic acid versus placebo. We found no statistically significant changes in the clinical parameters tested at the end of the 1 year trial, nor did we find any significant adverse events. Conclusions This study tested the hypothesis that by increasing the methylation of the UBE3A- antisense transcript in Angelman syndrome to promote expression of the silenced paternal UBE3A gene we may ameliorate the clinical phenotypes of AS. We treated two sets of identical twins with placebo versus betaine and folic acid. Although this study represented a novel approach to treating Angelman syndrome, the differences in the developmental testing results was not significant. This paper also discusses the value of monozygotic twin studies in minimizing confounding variables and its utility in conducting small treatment studies. Trial registration NCT00348933 . Registered 6 July 2006.

Biallelic pathogenic variants in NDUFS8, a nuclear gene encoding a subunit of mitochondrial complex I, result in a mitochondrial disorder characterized by varying clinical presentations and severity. Here, we expand the neuroimaging and clinical spectrum of NDUFS8‐related disorder. We present three cases from two unrelated families (a girl and two brothers) homozygous for a recurrent pathogenic NDUFS8 variant [c.460G>A, p.(Gly154Ser)], located in the [4Fe‐4S] domain of the protein. One of the patients developed auto‐antibody positive diabetic ketoacidosis. Brain MRIs performed in two of the three patients demonstrated diffuse cerebral and cerebellar white matter involvement including corticospinal tracts, but notably had sparing of deep gray matter structures. Our report expands the neuroimaging phenotype of NDUFS8‐related disorder to include progressive leukodystrophy with increasing brainstem and cerebellar involvement, with relative sparing of the basal ganglia. In addition, we describe autoimmune diabetes in association with NDUFS8‐related disorder, though the exact mechanism of this association is unclear. This paper provides a comprehensive review of case presentation and progressive neuroimaging findings of three patients from two unrelated families that have an identical pathogenic NDUFS8 variant, which expands the clinical spectrum of NDUFS8‐associated neurological disease.

Although norm-referenced scores are essential to the identification of disability, they possess several features which affect their sensitivity to change. Norm-referenced scores often decrease over time among people with neurodevelopmental disorders who exhibit slower-than-average increases in ability. Further, the reliability of norm-referenced scores is lower at the tails of the distribution, resulting in floor effects and increased measurement error for people with neurodevelopmental disorders. In contrast, the person ability scores generated during the process of constructing a standardized test with item response theory are designed to assess change. We illustrate these limitations of norm-referenced scores, and relative advantages of ability scores, using data from studies of autism spectrum disorder and creatine transporter deficiency.

Background:Segmental duplications at breakpoints (BP4–BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with mental retardation, epilepsy, and/or electroencephalogram (EEG) abnormalities.Patients:DNA samples from 1445 unrelated patients submitted consecutively for clinical array comparative genomic hybridisation (CGH) testing at Children’s Hospital Boston and DNA samples from 1441 individuals with autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository.Results:We report the clinical features of five patients with a BP4–BP5 deletion, three with a BP4–BP5 duplication, and two with an overlapping but smaller duplication identified by whole genome high resolution oligonucleotide array CGH. These BP4–BP5 deletion cases exhibit minor dysmorphic features, significant expressive language deficits, and a spectrum of neuropsychiatric impairments that include autism spectrum disorder, attention deficit hyperactivity disorder, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate mental retardation to normal IQ with learning disability. BP4–BP5 covers ∼1.5 Mb (chr15:28.719–30.298 Mb) and includes six reference genes and 1 miRNA gene, while the smaller duplications cover ∼500 kb (chr15:28.902–29.404 Mb) and contain three reference genes and one miRNA gene. The BP4–BP5 deletion and duplication events span CHRNA7, a candidate gene for seizures. However, none of these individuals reported here have epilepsy, although two have an abnormal EEG.Conclusions:The phenotype of chromosome 15q13.2q13.3 BP4–BP5 microdeletion/duplication syndrome may include features of autism spectrum disorder, a variety of neuropsychiatric disorders, and cognitive impairment. Recognition of this broader phenotype has implications for clinical diagnostic testing and efforts to understand the underlying aetiology of this syndrome.