Characterization of central manifestations in patients with Niemann-Pick disease type C.

PURPOSE: Niemann-Pick disease type C (NPC) is a rare lysosomal storage disease characterized by progressive neurodegeneration and neuropsychiatric symptoms. This study investigated pathophysiological mechanisms underlying motor deficits, particularly speech production, and cognitive impairment. METHODS: We prospectively phenotyped 8 adults with NPC and age-sex-matched healthy controls using a comprehensive assessment battery, encompassing clinical presentation, plasma biomarkers, hand-motor skills, speech production, cognitive tasks, and (micro-)structural and functional central nervous system properties through magnetic resonance imaging. RESULTS: Patients with NPC demonstrated deficits in fine-motor skills, speech production timing and coordination, and cognitive performance. Magnetic resonance imaging revealed reduced cortical thickness and volume in cerebellar subdivisions (lobule VI and crus I), cortical (frontal, temporal, and cingulate gyri) and subcortical (thalamus and basal ganglia) regions, and increased choroid plexus volumes in NPC. White matter fractional anisotropy was reduced in specific pathways (intracerebellar input and Purkinje tracts), whereas diffusion tensor imaging graph theory analysis identified altered structural connectivity. Patients with NPC exhibited altered activity in sensorimotor and cognitive processing hubs during resting-state and speech production. Canonical component analysis highlighted the role of cerebellar-cerebral circuitry in NPC and its integration with behavioral performance and disease severity. CONCLUSION: This deep phenotyping approach offers a comprehensive systems neuroscience understanding of NPC motor and cognitive impairments, identifying potential central nervous system biomarkers.

Insights into the genotype-phenotype relationship of ocular manifestations in Kabuki syndrome.

We aim to assess if genotype-phenotype correlations are present within ocular manifestations of Kabuki syndrome (KS) among a large multicenter cohort. We conducted a retrospective, medical record review including clinical history and comprehensive ophthalmological examinations of a total of 47 individuals with molecularly confirmed KS and ocular manifestations at Boston Children's Hospital and Cincinnati Children's Hospital Medical Center. We assessed information regarding ocular structural, functional, and adnexal elements as well as pertinent associated phenotypic features associated with KS. For both type 1 KS (KS1) and type 2 KS (KS2), we observed more severe eye pathology in nonsense variants towards the C-terminus of each gene, KMT2D and KDM6A, respectively. Furthermore, frameshift variants appeared to be not associated with structural ocular elements. Between both types of KS, ocular structural elements were more frequently identified in KS1 compared with KS2, which only involved the optic disc in our cohort. These results reinforce the need for a comprehensive ophthalmologic exam upon diagnosis of KS and regular follow-up exams. The specific genotype may allow risk stratification of the severity of the ophthalmologic manifestation. However, additional studies involving larger cohorts are needed to replicate our observations and conduct powered analyses to more formally risk-stratify based on genotype, highlighting the importance of multicenter collaborations in rare disease research.

A case of Aicardi syndrome associated with duplication event of Xp22 including SHOX.

BACKGROUND: Aicardi syndrome is a neurodevelopmental disorder characterized by a triad of partial or complete agenesis of the corpus callosum, infantile spasms, and pathognomonic chorioretinal lacunae. METHODS: Examination, multimodal imaging, and genetic testing were used to guide diagnosis. RESULTS: We report a case of a pediatric patient who was initially diagnosed with refractory infantile spasms. The patient was unresponsive to conventional antiepileptic therapy, and genetic testing with whole exome and mitochondrial genome sequencing could not identify the underlying cause, so vigabatrin was initiated. The ophthalmic examination under anesthesia for vigabatrin toxicity screening revealed chorioretinal atrophy in the retinal periphery of both eyes, with two 3-disc diameter chorioretinal lacunae superotemporal and inferonasal to the optic nerve in the left eye. Given the neuroimaging findings of corpus callosum hypoplasia with polymicrogyria and ocular findings, the patient was diagnosed with Aicardi syndrome. Genetic testing revealed a novel duplication event at the Xp22 locus. CONCLUSIONS: Aicardi syndrome, albeit a rare condition, should always be considered in the differential diagnosis when investigating a female child with refractory seizures in early childhood. Genetic testing may help further our understanding of AIS and the search for a genetic etiology.

From Genotype to Phenotype-A Review of Kabuki Syndrome.

Kabuki syndrome (KS) is a rare neuro-developmental disorder caused by variants in genes of histone modification, including KMT2D and KDM6A. This review assesses our current understanding of KS, which was originally named Niikawa-Kuroki syndrome, and aims to guide surveillance and medical care of affected individuals as well as identify gaps in knowledge and unmet patient needs. Ovid MEDLINE and EMBASE databases were searched from 1981 to 2021 to identify reports related to genotype and systems-based phenotype characterization of KS. A total of 2418 articles were retrieved, and 152 were included in this review, representing a total of 1369 individuals with KS. Genotype, phenotype, and the developmental and behavioral profile of KS are reviewed. There is a continuous clinical phenotype spectrum associated with KS with notable variability between affected individuals and an emerging genotype-phenotype correlation. The observed clinical variability may be attributable to differences in genotypes and/or unknown genetic and epigenetic factors. Clinical management is symptom oriented, fragmented, and lacks established clinical care standards. Additional research should focus on enhancing understanding of the burden of illness, the impact on quality of life, the adult phenotype, life expectancy and development of standard-of-care guidelines.

Targeting neurological abnormalities in lysosomal storage diseases.

Central nervous system (CNS) abnormalities and corresponding neurological and psychiatric symptoms are frequently observed in lysosomal storage disorders (LSDs). The genetic background of individual LSDs is indeed unique to each illness. However, resulting defective lysosomal function within the CNS can transition normal cellular processes (i.e., autophagy) into aberrant mechanisms, facilitating overlapping downstream consequences including neurocircuitry dysfunction, neurodegeneration as well as sensory, motor, cognitive, and psychological symptoms. Here, the neurological and biobehavioral phenotypes of major classes of LSDs are discussed alongside therapeutic strategies in development that aim to tackle neuropathology among other disease elements. Finally, focused ultrasound blood-brain barrier opening is proposed to enhance therapeutic delivery thereby overcoming the key hurdle of central distribution of disease modifying therapies in LSDs.

Congenital microgastria-limb reduction association: A case report and review of the literature.

We report a patient with phenotypic semblance to the congenital microgastria-limb reduction association (MLRD). Our patient presented with microgastria, bilateral upper limb anomalies, asplenia, solitary kidney, and mild micrognathia. In addition to the anomalies seen in our patient, MLRD has been associated with respiratory, cardiovascular, and central nervous system anomalies. MLRD is thought to arise from a developmental field defect during embryonic weeks five and six; however, no genetic cause has been elucidated. Along with our patient presentation, we review the literature to further our understanding of the MLRD phenotype spectrum.

Author Correction: Clinical Validation of Targeted and Untargeted Metabolomics Testing for Genetic Disorders: A 3 Year Comparative Study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Clinical Validation of Targeted and Untargeted Metabolomics Testing for Genetic Disorders: A 3 Year Comparative Study.

Global untargeted metabolomics (GUM) has entered clinical diagnostics for genetic disorders. We compared the clinical utility of GUM with traditional targeted metabolomics (TM) as a screening tool in patients with established genetic disorders and determined the scope of GUM as a discovery tool in patients with no diagnosis under investigation. We compared TM and GUM data in 226 patients. The first cohort (n = 87) included patients with confirmed inborn errors of metabolism (IEM) and genetic syndromes; the second cohort (n = 139) included patients without diagnosis who were undergoing evaluation for a genetic disorder. In patients with known disorders (n = 87), GUM performed with a sensitivity of 86% (95% CI: 78-91) compared with TM for the detection of 51 diagnostic metabolites. The diagnostic yield of GUM in patients under evaluation with no established diagnosis (n = 139) was 0.7%. GUM successfully detected the majority of diagnostic compounds associated with known IEMs. The diagnostic yield of both targeted and untargeted metabolomics studies is low when assessing patients with non-specific, neurological phenotypes. GUM shows promise as a validation tool for variants of unknown significance in candidate genes in patients with non-specific phenotypes.

A defect in the inner kinetochore protein CENPT causes a new syndrome of severe growth failure.

Primordial growth failure has been linked to defects in the biology of cell division and replication. The complex processes involved in microtubule spindle formation, organization and function have emerged as a dominant patho-mechanism in these conditions. The majority of reported disease genes encode for centrosome and centriole proteins, leaving kinetochore proteins by which the spindle apparatus interacts with the chromosomes largely unaccounted for. We report a novel disease gene encoding the constitutive inner kinetochore member CENPT, which is involved in kinetochore targeting and assembly, resulting in severe growth failure in two siblings of a consanguineous family. We herein present studies on the molecular and cellular mechanisms that explain how genetic mutations in this gene lead to primordial growth failure. In both, affected human cell lines and a zebrafish knock-down model of Cenpt, we observed aberrations in cell division with abnormal accumulation of micronuclei and of nuclei with increased DNA content arising from incomplete and/or irregular chromosomal segregation. Our studies underscore the critical importance of kinetochore function for overall body growth and provide new insight into the cellular mechanisms implicated in the spectrum of these severe growth disorders.

Newborn Screening for Pompe Disease.

Started in 1963 by Robert Guthrie, newborn screening (NBS) is considered to be one of the great public health achievements. Its original goal was to screen newborns for conditions that could benefit from presymptomatic treatment, thereby reducing associated morbidity and mortality. With advances in technology, the number of disorders included in NBS programs increased. Pompe disease is a good candidate for NBS. Because decisions regarding which diseases should be included in NBS panels are made regionally and locally, programs and efforts for NBS for Pompe disease have been inconsistent both in the United States and globally. In this article, published in the "Newborn Screening, Diagnosis, and Treatment for Pompe Disease" guidance supplement, the Pompe Disease Newborn Screening Working Group, an international group of experts in both NBS and Pompe disease, review the methods used for NBS for Pompe disease and summarize results of current and ongoing NBS programs in the United States and other countries. Challenges and potential drawbacks associated with NBS also are discussed.

Newborn Screening for Lysosomal Storage Disorders.

Newborn screening is one of the most important public health initiatives to date, focusing on the identification of presymptomatic newborn infants with treatable conditions to reduce morbidity and mortality. The number of screening conditions continues to expand due to advances in screening technologies and the development of novel therapies. Consequently, some of the lysosomal storage disorders are now considered as candidates for newborn screening, although many challenges including identification of late-onset phenotypes remain. This review provides a critical appraisal of the current state of newborn screening for lysosomal storage disorders.

Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.

Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.

Epidemiology and diagnosis of lysosomal storage disorders; challenges of screening.

The lysosomal storage disorders (LSDs) are a group of genetic disorders resulting from defective lysosomal metabolism and subsequent accumulation of substrates. Patients present with a large phenotypic spectrum of disease manifestations that are generally not specific for LSDs, leading to considerable diagnostic delay and missed cases. Introduction of new disease modifying therapies for LSDs has made early diagnosis a priority. Increased awareness, but particularly the introduction of screening programs allow for early diagnosis and timely initiation of treatment. This review will provide insight into the epidemiology and diagnostic process for LSDs. In addition, challenges for carrier screening, high-risk screening and newborn population screening for LSDs are discussed.

Diagnosing lysosomal storage disorders: mucopolysaccharidosis type I.

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder due to deficiency of alpha iduronidase (IDUA). Progressive storage of dermatan and heparan sulfate throughout the body lead to a multiorgan presentation including short stature, dysostosis multiplex, corneal clouding, hearing loss, coarse facies, hepatosplenomegaly, and intellectual disability. Diagnosis of MPS I is based on IDUA enzyme analysis in leukocytes or dried blood spots (DBS) followed by molecular confirmation of the IDUA gene mutations in individuals with low enzyme activity. The advent of mass spectrometry methods for enzyme analysis in DBS has enabled high-throughput screening for MPS I in symptomatic individuals and newborn infants. The following unit provides the detailed analytical protocol for measurement of IDUA activity in DBS using tandem mass spectrometry.

The laboratory diagnosis of mucopolysaccharidosis III (Sanfilippo syndrome): A changing landscape.

Mucopolysaccharidosis type III (MPS III) is characterized by progressive neurological deterioration, behavioral abnormalities, a relatively mild somatic phenotype, and early mortality. Because of the paucity of somatic manifestations and the rarity of the disease, early diagnosis is often difficult. Therapy targeting the underlying disease pathophysiology may offer the greatest clinical benefit when started prior to the onset of significant neurologic sequelae. Here we review current practices in the laboratory diagnosis of MPS III in order to facilitate earlier patient identification and diagnosis. When clinical suspicion of MPS III arises, the first step is to order a quantitative assay that screens urine for the presence of glycosaminoglycan biomarkers using a spectrophotometric compound (e.g., dimethylmethylene blue). We recommend testing all patients with developmental delay and/or behavioral abnormalities as part of the diagnostic work-up because quantitative urine screening is inexpensive and non-invasive. Semi-quantitative urine screening assays using cationic dyes on filter paper (e.g., spot tests) have relatively high rates of false-positives and false-negatives and are obsolete. Of note, a negative urinary glycosaminoglycan assay does not necessarily rule out MPS because, in some patients, an overlap in excretion levels with healthy controls may occur. All urine samples that test positive for glycosaminoglycans with a quantitative assay should be confirmed by electrophoresis, thin layer chromatography, or tandem mass spectrometry, which further improves the sensitivity and specificity. The gold standard for diagnosis remains the enzyme activity assay in cultured skin fibroblasts, leukocytes, plasma, or serum, which can be used as a first-line diagnostic test in some regions. Molecular genetic analysis should be offered to all families of patients to allow genetic counseling for informed family planning. For a small number of variants, genotype-phenotype correlations are available and can offer prognostic value. Prenatal testing via enzyme activity assay in chorionic villi or amniotic fluid cells is available at a limited number of centers worldwide, but whenever possible, a molecular genetic analysis is preferred for prenatal diagnosis. To conclude, we discuss the development of newborn screening assays in dried blood spots and high-throughput methods for sequencing the protein-coding regions of the genome (whole exome sequencing) and their relevance to future changes in the MPS III diagnostic landscape.

Bridging the gaps between the histopathological and demographic risk factors of preterm birth in a unique Miami inner-city population.

We aim to identify the link between placental histological findings and obstetric reports to determine possible risk factors of spontaneous preterm birth (SPTB). We prospectively ascertained birth records and outcomes from all deliveries in our hospital in 1 year. Records were used to determine and stratify for either full-term or preterm [spontaneous or indicated (I)] deliveries. We analyzed for risk factor association using χ(2) tests and common odds ratio estimates (SPSS v21.0). Our cohort totaled 6088 deliveries: 236 IPTB, 43 SPTB, and 5809 term births. Largely Hispanic, we determined race, parity, prenatal care access, preeclampsia, gestational diabetes, and BMI to be highly associated with SPTB (p < 0.01). Histologically, placentas of women with SPTB were twice as likely to have chronic villitis. We found that chronic villitis is associated with SPTB. Results of this study can be used in increasing the understanding of SPTB.

Patients with type 1 Gaucher disease in South Florida, USA: demographics, genotypes, disease severity and treatment outcomes.

BACKGROUND: Gaucher disease, an autosomal recessive condition due to deficiency of lysosomal glucocerebrosidase, is a multisystemic disease, with variable age of onset, severity and progression. It is classified into subtypes delineated by the absence (type 1) or presence (type 2 and 3) of primary nervous system involvement. The ethnically diverse, largely immigrant population in South Florida has a spectrum of Gaucher disease phenotypes, creating a challenge for optimization of disease management and an opportunity to explore treatment patterns. METHODS: Ninety-three records from patients with Gaucher type I in South Florida were retrieved from the International Collaborative Gaucher Group (ICGG) Registry. Individual genotypes were correlated with severity scores and success at achieving published therapeutic goals for haemoglobin concentration, platelet count, spleen volume, liver volume and amelioration of bone pain and bone crises. RESULTS: The majority of patients were diagnosed during the fifth decade of life. Almost two-thirds were homozygous for the N370S mutation, reflecting the large Ashkenazi Jewish population in South Florida. The majority received imiglucerase (62.8%) at various intervals. 24.5% of patients underwent splenectomy before starting enzyme replacement therapy. After a median 12 treatment years, South Florida patients matched or exceeded the ICCG 4 year therapeutic goal achievement for platelet count (85.4% vs. 79.6% success), spleen volume (93.3% vs. 78.0% success), liver volume (93.4% vs. 90.6% success), and bone crises (100% vs. 99% success). Nevertheless, fewer patients with intact spleens had sustained achievement of all 6 therapeutic goals (30.4% versus 41.4%) and only 40% of the splenectomy patients sustained achievement of 5/5 possible goals. 54.7% of the intact spleen patients continued to have bone pain vs. 29.8% in ICCG. Significantly, only 37% of the ICGG patient cohort had bone pain prior to initiation of treatment compared to 73.4% of the South Florida patients (moderate or severe pain in 59.6%). CONCLUSIONS: Demographic characteristics are a significant determinant of the differences in response to treatment observed in South Florida Gaucher patients compared to those described in the international population enrolled in the ICGG Gaucher Registry. Individual genotypes and ethnic background are important considerations for optimizing patient care for Gaucher disease.