variants cause lysosomal and autophagic defects resulting in a hypomyelinating leukodystrophy with epileptic encephalopathy.

encodes a subunit shared by the BLOC-1 and BORC hetero-octameric complexes that regulate various endolysosomal processes. Here, we report the identification of seven distinct variants in in eleven individuals from seven independent families presenting with early psychomotor delay, hypotonia, spasticity, epileptic encephalopathy, optic atrophy, and leuko-axonopathy with hypomyelination. A subset of the affected individuals also have features of hypopigmentation and ocular albinism that are similar, although milder, than those of individuals with BLOC-1-related Hermansky-Pudlak syndrome.

Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.

Background: PPCS deficiency disorder (PPCS DD) is an ultra-rare, autosomal recessive form of dilated cardiomyopathy (DCM) caused by pathogenic variants in PPCS, which encodes the enzyme catalyzing the second step in the coenzyme A (CoA) biosynthesis pathway. To date, only six patients worldwide have been identified.

Methods: Whole-exome sequencing was performed to identify pathogenic PPCS variants in affected individuals.

CLN3 disease disrupts very early postnatal hippocampal maturation.

CLN3 disease or juvenile neuronal ceroid lipofuscinosis (Batten disease), is a progressive, severe, neurodegenerative, lysosomal storage disorder. Previous studies have demonstrated that network-level excitability differences are present in mouse models prior to significant lysosomal storage accumulation. Here we sought to identify the earliest biochemical and functional markers of disease in the hippocampus, a brain region important in learning and memory and implicated in CLN3 disease.

Rothmund-Thomson Syndrome Type 2 in an African American/Puerto Rican Child Demonstrates Diagnostic Challenges in Diverse Population.

Rothumnd-Thomson syndrome (RTS) is a rare genetic condition characterized by poikiloderma, sparse hair, short stature, skeletal abnormalities, cataracts, and increased risk for malignancies. The presenting symptom is often a classic rash with erythema on the cheeks and face with spread to extensor surfaces of extremities. Gradually over months to years, this rash develops into poikiloderma (reticulated hyper- and hypopigmentation, telangiectasias, and areas of punctate atrophy).

Truncating Variants in RREB1 Cause a Novel RASopathy Syndrome of Congenital Heart Disease, Genitourinary Malformations, and Developmental Delay.

The interstitial 6p microdeletion syndrome is characterized by dysmorphic facies and structural heart, kidney, brain, and musculoskeletal differences. RREB1 haploinsufficiency and consequent abnormal RAS-MAPK pathway signaling have been proposed as a driver of the disease phenotype; however, apart from a single case report, the phenotype of intragenic RREB1 variants is unknown. Here we present a cohort of 6 individuals with truncating RREB1 variants.

Exploration Into Lived Experiences of Multiple Sulfatase Deficiency-Affected Individuals and Their Families.

Despite their importance, rare diseases' impact on patients and families is understudied. This is particularly true for ultrarare disorders, such as multiple sulfatase deficiency (MSD), a pediatric neurodegenerative disorder. To address this gap, we captured caregiver perspectives on how multiple sulfatase deficiency affects their child, themselves, and their families regarding adaptive behaviors and health-related quality of life.

Current clinical applications of AAV-mediated gene therapy.

Currently, there are an estimated 8,000 genetic disorders that cumulatively affect approximately 10% of the population. Even among the 5% of patients with genetic disease that have treatment options, these therapeutics rarely address the underlying cause of disease but rather focus on managing or modifying symptoms and typically require recurrent, lifelong therapy. A therapeutic approach to genetic disease that in vivo delivers a functional copy of the aberrant gene is an intuitive solution that has thus far taken 3 decades to reduce to clinical practice, predominantly using adeno-associated viral (AAV) vectors.

Coupling deep phenotypic quantification with next-generation phenotyping for 192 individuals with germline histonopathies.

Mendelian histonopathies are rare neurodevelopmental disorders (NDDs) caused by germline variants in histone-encoding genes. Here, we perform a more expansive pan-histonopathy interrogation than previously possible. We analyze data from 192 individuals affected by histonopathies.

Effective gene therapy for metachromatic leukodystrophy achieved with minimal lentiviral genomic integrations.

Metachromatic leukodystrophy (MLD) is a fatal lysosomal storage disease characterized by the deficient enzymatic activity of arylsulfatase A (ARSA). Combined autologous hematopoietic stem cell transplantion (HSCT) with lentiviral (LV)-based gene therapy has great potential to treat MLD. Achieving the optimal balance between high enzyme production for therapeutic efficacy and maintaining a low vector copy number (VCN) is crucial.

Five-Year Outcomes of Patients with Pompe Disease Identified by the Pennsylvania Newborn Screen.

Pennsylvania started newborn screening for Pompe disease (PD) in 2016. As a result, the prevalence of PD has increased with early detection, primarily of late-onset Pompe disease (LOPD). No clear guidelines exist regarding if and when to initiate enzyme replacement therapy (ERT) in patients identified through a newborn screen (NBS).

MBOAT7 encephalopathy: Characterizing the neurology and epileptology.

Objective: Biallelic pathogenic MBOAT7 variants are associated with neurodevelopmental disorders, intellectual disability (ID), epilepsy, and neuropsychiatric disorders such as attention-deficit/hyperactivity disorder and autism spectrum disorders. We aimed to characterize the epilepsy phenotype in a cohort of patients affected by this syndrome.

Methods: We describe epilepsy features, electroencephalography, magnetic resonance imaging (MRI) findings, antiseizure treatment response, and neurodevelopment of 15 patients with biallelic MBOAT7 variants.

Branched Chain Amino Acid Metabolism in Developmental Brain Injury: Putative Mechanisms and Therapeutic Potential.

Background: Branched chain amino acid (BCAA) metabolism plays roles in various cellular processes, including energy homeostasis, anabolic signaling, and production of glutamate, the primary excitatory neurotransmitter. Emerging evidence also suggests BCAA metabolism has relationships to inflammatory and hypoxic cellular responses. Recent work in adult and adolescent clinical populations has suggested that BCAA dietary supplementation may improve outcomes associated with traumatic brain injury.

Functional connectivity changes in mouse models of maple syrup urine disease.

Maple syrup urine disease is a rare metabolic disorder that results in neurodevelopmental injury despite dietary therapy. While structural neuroimaging has shown a characteristic pattern of edema and white matter injury, no functional neuroimaging studies of maple syrup urine disease have been performed. Using widefield optical imaging, we investigated resting-state functional connectivity in two brain-specific mouse models of maple syrup urine disease (an astrocyte-specific knockout and a whole-brain knockout).

Gene therapies for neurogenetic disorders.

Pathogenic variants in over 1700 genes can cause neurogenetic disorders. Monogenetic diseases are ideal targets for genetic therapies; however, the blood-brain barrier (BBB), post-mitotic neurons, and inefficient delivery platforms make gene therapies for neurogenetic diseases challenging. Following nusinersen's 2016 approval, the development of gene therapies for neurogenetic disorders has advanced rapidly, with new delivery vehicles [e.

Contribution of Brain Intrinsic Branched-Chain Amino Acid Metabolism in a Novel Mouse Model of Maple Syrup Urine Disease.

Maple syrup urine disease (MSUD) results from loss of branched-chain ketoacid dehydrogenase (BCKDH) activity, the committed, rate-limiting step of branched-chain amino acid (BCAA) oxidation. Current treatments, including a low protein diet and liver transplantation, improve peripheral biochemistry and limit episodes of metabolic decompensation but do not fully prevent chronic neuropsychiatric symptoms. The mechanisms underlying chronic neurologic phenotypes remain poorly understood.

Longitudinal outcomes in Noonan syndrome.

Purpose: Noonan syndrome and related disorders (NS) are multisystemic conditions affecting approximately 1:1000 individuals. Previous natural history studies were conducted before widespread comprehensive genetic testing. This study provides updated longitudinal natural history data in participants with molecularly confirmed NS.

Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.

The heart employs a specialized ribosome in its muscle cells to translate genetic information into proteins, a fundamental adaptation with an elusive physiological role. Its significance is underscored by the discovery of neonatal patients suffering from often fatal heart failure caused by severe dilated cardiomyopathy when both copies of the gene are mutated. RPL3L is a muscle-specific paralog of the ubiquitous ribosomal protein L3 (RPL3), which makes the closest contact of any protein to the ribosome's RNA-based catalytic center.

Bone marrow transplantation reverses metabolic alterations in multiple sulfatase deficiency: a case series.

Background: Multiple sulfatase deficiency (MSD) is an exceptionally rare neurodegenerative disorder due to the absence or deficiency of 17 known cellular sulfatases. The activation of all these cellular sulfatases is dependent on the presence of the formylglycine-generating enzyme, which is encoded by the SUMF1 gene. Disease-causing homozygous or compound heterozygous variants in SUMF1 result in MSD.

Bone marrow transplantation increases sulfatase activity in somatic tissues in a multiple sulfatase deficiency mouse model.

Background: Multiple Sulfatase Deficiency (MSD) is an ultra-rare autosomal recessive disorder characterized by deficient enzymatic activity of all known sulfatases. MSD patients frequently carry two loss of function mutations in the SUMF1 gene, encoding a formylglycine-generating enzyme (FGE) that activates 17 different sulfatases. MSD patients show common features of other lysosomal diseases like mucopolysaccharidosis and metachromatic leukodystrophy, including neurologic impairments, developmental delay, and visceromegaly.

Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction.

Neonatal dilated cardiomyopathy (DCM) is a poorly understood muscular disease of the heart. Several homozygous biallelic variants in LMOD2, the gene encoding the actin-binding protein Leiomodin 2, have been identified to result in severe DCM. Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and decreased heart contractility, often resulting in neonatal death.