Movement Disorder Following Hypoglycemic Encephalopathy in Mitochondrial 3-Hydroxy-3-methylglutaryl-CoA Synthase-2 (mHS) Deficiency.

Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (mHS) deficiency is an ultra-rare inborn error of ketone body synthesis that is caused by biallelic mutations in . The manifestations of mHS deficiency can include hypoketotic hypoglycemia, metabolic acidosis, lethargy, encephalopathy, hyperammonemia, and hepatomegaly. Here, we report a case of movement disorder following hypoglycemic encephalopathy involving the basal ganglia in a patient with mHS deficiency.

Heterozygosity in NPC may be associated with neurologic and systemic phenotypes.

Background: Niemann-Pick disease type C (NPC) is a pan-ethnic, progressive, recessively inherited lysosomal disorder that affects 1:100,000 live births. Emerging biochemical, genetic, and clinical evidence challenges the traditional view that disease-associated variants in the genes associated with the typical phenotype NPC manifest as an exclusively autosomal recessive disorder. While biallelic pathogenic variants cause the NPC disease phenotype, heterozygous carriers may exhibit phenotypic traits attributable to a partial loss of or function.

A National Survey on the Neurogenetics Workforce: Practice Models, Evolving Challenges, and Future Directions.

Background: Neurogeneticists are specialized providers who focus on diagnosing and managing genetic disorders affecting the nervous system. Training pathways for neurogeneticists vary, including dual residencies in neurology and genetics, one-year fellowships, or extensive clinical experience. This diversity reflects the expanding applications of neurogenomics across neurology.

The Complexity of Familial Inheritance in Pectus Excavatum: A Ten-Family Exome Sequencing Analysis.

: Pectus excavatum (PEx) is considered, at least partially, a familial disorder. A variety of inheritance patterns, associations with genetic syndromes, and pathogenic variants have been reported. However, the etiology of this condition is still not completely understood, and no known genes have been identified as definitive contributors.

Diagnostic yield of exome and genome sequencing after non-diagnostic multi-gene panels in patients with single-system diseases.

Background: Though next-generation sequencing (NGS) tests like exome sequencing (ES), genome sequencing (GS), and panels derived from exome and genome data (EGBP) are effective for rare diseases, the ideal diagnostic approach is debated. Limited research has explored reanalyzing raw ES and GS data post-negative EGBP results for diagnostics.

Results: We analyzed complete ES/GS raw sequencing data from Mayo Clinic's Program for Rare and Undiagnosed Diseases (PRaUD) patients to assess whether supplementary findings could augment diagnostic yield.

Semiautomated approach focused on new genomic information results in time and effort-efficient reannotation of negative exome data.

Most rare disease patients (75-50%) undergoing genomic sequencing remain unsolved, often due to lack of information about variants identified. Data review over time can leverage novel information regarding disease-causing variants and genes, increasing this diagnostic yield. However, time and resource constraints have limited reanalysis of genetic data in clinical laboratories setting.

Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions.

Adult-onset leukodystrophies though individually rare are not uncommon. This group includes several disorders with isolated adult presentations, as well as several childhood leukodystrophies with attenuated phenotypes that present at a later age. Misdiagnoses often occur due to the clinical and radiological overlap with common acquired disorders such as infectious, immune, inflammatory, vascular, metabolic, and toxic etiologies.

Retinal Vasculopathy With Cerebral Leukoencephalopathy and Systemic Manifestations: Critical Role of Retina Specialists.

Purpose: To describe a case of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) to enhance early recognition of this often-missed diagnosis.

Methods: A case report is presented.

Results: A 50-year-old woman with a history of Raynaud phenomenon, memory difficulties, and a family history of strokes was referred for evaluation of a bilateral, small-vessel, occlusive disease refractory to immunosuppressive therapy.

Marfan Syndrome Presenting as Spontaneous Coronary Artery Dissection and Arteriopathy.

Introduction: Spontaneous coronary artery dissection (SCAD) is a term used to define a spontaneous separation of the coronary artery wall not related to underlying risk factors, such as trauma or underlying atherosclerotic disease. While SCAD has a range of different etiologies, with fibromuscular dysplasia being the most common, most cases of SCAD have no concomitant arteriopathy.

Case Report: Here we describe a case of a patient who presented to our institution with SCAD and evidence of an asymptomatic arteriopathy involving extracranial segments of the carotid and vertebral arteries, later found to have a pathogenic variant in the FBN1 gene and ultimately diagnosed with Marfan syndrome.

Neurofibromatosis 1 in the setting of dual diagnosis: Diagnostic and management conundrums.

Neurofibromatosis type 1 (NF1) is a common neurocutaneous disorder characterized by development of pigmentary skin changes, neurogenic tumors, and other manifestations involving multiple organ systems. Penetrance is complete, though expressivity is quite variable even among the family members. Given that NF1 is a common hereditary condition, existence of a second genetic disorder in NF1 patients is not unexpected.

Familial variability of cerebrotendinous xanthomatosis lacking typical biochemical findings.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis caused by pathogenic variants in the gene encoding the mitochondrial enzyme sterol 27-hydroxylase. Patients with CTX can present with a wide range of symptoms, but most often have evidence of tendon xanthomas along with possible cataracts, atherosclerosis, or neurological dysfunction. Regardless of clinical phenotype, CTX patients typically exhibit levels of cholestanol and bile acid precursors in the circulation that are many fold increased over normal control concentrations.

Recurrent ganglioneuroma in PTPN11-associated Noonan syndrome: A case report and literature review.

Noonan syndrome (NS) is an autosomal dominant condition with variable expressivity most commonly due to a germline pathogenic variant in PTPN11, which encodes the protein tyrosine phosphatase SHP-2. Gain-of-function variants in PTPN11 are known to promote oncogenic behavior in affected tissues. We report the clinical description of a young adult male presenting with relapsing ganglioneuromas, dysmorphic features, cardiac abnormalities, and multiple lentigines, strongly suspicious for NS.

LZTR1-related spinal schwannomatosis and 7q11.23 duplication syndrome: A complex phenotype with dual diagnosis.

Background: Dual diagnoses in genetics practice are not uncommon and patients with dual diagnosis often present with complex and challenging phenotypes. A combination of meticulous phenotyping and molecular genetic techniques are essential in solving these diagnostic odysseys.

Methods: Clinical features and genetic workup of a patient presenting with incidental schwannomatosis.

Impact of integrated translational research on clinical exome sequencing.

Purpose: Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing.

Interpretation challenges of novel dual-class missense and splice-impacting variant in POLR3A-related late-onset hereditary spastic ataxia.

Background: RNA polymerase III (Pol III)-related disorders are autosomal recessive neurodegenerative disorders caused by variants in POLR3A or POLR3B. Recently, a novel phenotype of adult-onset spastic ataxia was identified in individuals with the c.1909+22G>A POLR3A variant in compound heterozygosity.

Hepatic Steatosis Resulting From -Associated Familial Lipodystrophy.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, with potential causes stemming from obesity, metabolic syndrome, genetic disorders, and drug toxicity. We report a 42-year-old woman with lipodystrophy and NAFLD due to a pathogenic variant in the (D300N) gene. This case report attempts to encourage clinicians to consider genetic diseases, specifically lipodystrophies, when working up uncommon causes of NAFLD.