A late presentation of TPM3 myopathy presenting as sleep hypoventilation in the setting of acute demyelinating encephalomyelitis.

Central hypoventilation is a rare cause of respiratory failure that has been associated with multiple underlying disorders, including congenital central hypoventilation syndrome, obesity hypoventilation syndrome, and several neuromuscular conditions. We report the case of an adolescent who presented with respiratory failure in the setting of acute demyelinating encephalomyelitis whose clinical history was consistent with a congenital myopathy and whom we found to have a Tropomyosin 3 (TPM3) genetic variant on further genetic testing. This case expands the clinical spectrum of causes for late-onset central hypoventilation in the setting of a neuromuscular disorder. CITATION: Stringel V, Bizargity P, Laureta E, Kothare S. A late presentation of TPM3 myopathy presenting as sleep hypoventilation in the setting of acute demyelinating encephalomyelitis. J Clin Sleep Med. 2022;18(11):2695-2698.

Newborn Screening for Spinal Muscular Atrophy in New York State: Clinical Outcomes From the First 3 Years.

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) was added to the Recommended Uniform Screening Panel (RUSP) in July 2018, largely on the basis of the availability and efficacy of newly-approved disease modifying therapies. New York State (NYS) started universal newborn screening for SMA in October 2018. The authors report the findings from the first 3 years of screening. METHODS: Statewide neonatal screening was conducted using DNA extracted from dried blood spots using a real-time quantitative polymerase chain reaction (qPCR) assay. Retrospective follow-up data were collected from 9 referral centers across the state on 34 infants. RESULTS: In the first three years since statewide implementation, nearly 650,000 infants have been screened for SMA. 34 babies screened positive and were referred to a neuromuscular specialty care center. The incidence remains lower than previously predicted. The majority (94%), including all infants with 2-3 copies of SMN2, have received treatment. Among treated infants, the overwhelming majority (97%; 29/30) have received gene replacement. All infants in this cohort with 3 copies of SMN2 are clinically asymptomatic post-treatment based on early clinical follow-up data. Infants with 2 copies of SMN2 are more variable in their outcomes. Electrodiagnostic outcomes data from a subgroup of patients (n=11) for whom pre- and post-treatment data demonstrated either improvement or no change in CMAP amplitude at last clinical follow-up compared to pre-treatment baseline. Most infants were treated before 6 weeks of age (median = 34.5 DOL; range 11-180). Delays and barriers to treatment identified by treating clinicians followed two broad themes: medical and non-medical. Medical delays most commonly reported were presence of AAV9 antibodies and elevated troponin I levels. Non-medical barriers included delays in obtaining insurance as well as insurance policies regarding specific treatment modalities. DISCUSSION: The findings from the NYS cohort of newborn screen-identified infants are consistent with other reports of improved outcomes from early diagnosis and treatment. Additional biomarkers of motor neuron health including electromyography can potentially be helpful in detecting pre-clinical decline.

Implementation of population-based newborn screening reveals low incidence of spinal muscular atrophy.

PURPOSE: Spinal muscular atrophy (SMA) was added to the Recommended Uniform Screening Panel (RUSP) in July 2018, following FDA approval of the first effective SMA treatment, and demonstration of feasibility of high-throughput newborn screening using a primary molecular assay. SMA newborn screening was implemented in New York State (NYS) on 1 October 2018. METHODS: Screening was conducted using DNA extracted from dried blood spots with a multiplex real-time quantitative polymerase chain reaction (qPCR) assay targeting the recurrent SMN1 exon 7 gene deletion. RESULTS: During the first year, 225,093 infants were tested. Eight screened positive, were referred for follow-up, and confirmed to be homozygous for the deletion. Infants with two or three copies of the SMN2 gene, predicting more severe, earlier-onset SMA, were treated with antisense oligonucleotide and/or gene therapy. One infant with ≥4 copies SMN2 also received gene therapy. CONCLUSION: Newborn screening permits presymptomatic SMA diagnosis, when treatment initiation is most beneficial. At 1 in 28,137 (95% confidence interval [CI]: 1 in 14,259 to 55,525), the NYS SMA incidence is 2.6- to 4.7-fold lower than expected. The low SMA incidence is likely attributable to imprecise and biased estimates, coupled with increased awareness, access to and uptake of carrier screening, genetic counseling, cascade testing, prenatal diagnosis, and advanced reproductive technologies.

Neuropathic cachexia associated with type 1 diabetes in an adolescent girl.

BACKGROUND: Diabetic neuropathic cachexia is a rare and little understood variant of diabetic neuropathy. It predominantly affects men with type 2 diabetes mellitus in their sixth to seventh decades of life and is characterized by the subacute onset of a painful sensory neuropathy, rapid weight loss, and psychiatric comorbidity. METHODS: We present the only female pediatric case described to date, and one of only a handful of cases reported to affect type 1 diabetics. RESULTS: In this patient a diagnosis of diabetic neuropathic cachexia was based on the rapid onset of severe allodynic pain, polyneuropathy, and marked weight loss in the setting of poorly controlled diabetes, without evidence of end-organ disease and exclusion of other known causes of neuropathy. CONCLUSIONS: Diabetic neuropathic cachexia is a complex neuroendocrinologic disorder characterized by profound weight loss, neuropathic pain, and mood disturbance. Electrodiagnostic abnormalities were pronounced showing a moderately severe generalized sensorimotor polyneuropathy.

CACNA1A nonsense mutation is associated with basilar-type migraine and episodic ataxia type 2.

Mutations in the CACNA1A gene on chromosome 19 have been associated with a variety of clinical disorders, including familial hemiplegic migraine type 1 and episodic ataxia type 2 (EA2). We report a patient with 2 distinct attack types, one representing EA2 and the other, basilar-type migraine. Genetic testing revealed a novel nonsense mutation in the CACNA1A gene at codon position 583. Treatment with acetazolamide relieved both types of attacks. We hypothesize that the CACNA1A gene mutation may contribute to both typical EA2 and typical basilar-type migraine, extending the spectrum of clinical manifestations associated with CACNA1A mutations.

A neonate with asymmetric arm movements.

Abnormal arm posture or movements in a neonate may cause significant concern in a pediatric emergency department. This can be secondary to osteomyelitis, which may rarely present with asymmetric arm movements in the neonatal period. The diagnosis of osteomyelitis is difficult to establish in a neonate because systemic signs may not be present at this age. We report an infant with upper limb weakness and asymmetric movements 3 weeks after delivery.

An asthmatic adolescent with a rash and eosinophilia.

Children frequently visit emergency departments with asthma exacerbations. Many of these asthmatic children may have fever and/or pneumonia, but when associated with eosinophilia or evidence of vasculitis, other diagnoses should be considered. Churg-Strauss syndrome is a rare form of systemic vasculitis, which usually occurs in patients with asthma in association with eosinophilia. The diagnosis of Churg-Strauss syndrome can be difficult because this syndrome may arise at first as a common association between asthma and allergic rhinitis. A delay in diagnosis and treatment may increase the morbidity from the complications of vasculitis. We report a young asthmatic adolescent who presented with vasculitis, eosinophilia, and peripheral neuropathy.

A febrile child with seizure and hemiparesis.

Febrile seizures are the most common neurological disorders in children and are among the more common symptoms that lead to an emergency department visit. Although most febrile seizures are simple and benign, these seizures can infrequently create a diagnostic dilemma. The diagnosis of cerebral venous thrombosis is challenging to emergency physicians because it can mimic the presentation of many other disorders, including ischemic and hemorrhagic stroke, tumor, and abscess. In addition, the broad variety of signs and symptoms makes the clinical diagnosis difficult. The patients may be presented with signs of increased intracranial pressure or focal neurological deficits. It is an uncommon but potentially dangerous cause of hemiparesis after seizure. Early recognition of this condition and appropriate management may reduce the mortality rate. We present a young child with dural sinus thrombosis who presented with seizures associated with fever and subsequent hemiparesis, and explained a possible mechanism of focal neurological deficit.