Long-term clinical observation of patients with heterozygous KIF1A variants.

KIF1A-related disorders (KRDs) encompass recessive and dominant variants with wide clinical variability. Recent genetic investigations have expanded the clinical phenotypes of heterozygous KIF1A variants. However, there have been a few long-term observational studies of patients with heterozygous KIF1A variants. A retrospective chart review of consecutive patients diagnosed with spastic paraplegia at Miyagi Children's Hospital from 2016 to 2020 identified six patients with heterozygous KIF1A variants. To understand the long-term changes in clinical symptoms, we examined these patients in terms of their characteristics, clinical symptoms, results of electrophysiological and neuroimaging studies, and genetic testing. The median follow-up period was 30 years (4-44 years). This long-term observational study showed that early developmental delay and equinus gait, or unsteady gait, are the first signs of disease onset, appearing with the commencement of independent walking. In addition, later age-related progression was observed in spastic paraplegia, and the appearance of axonal neuropathy and reduced visual acuity were characteristic features of the late disease phenotype. Brain imaging showed age-related progression of cerebellar atrophy and the appearance of hyperintensity of optic radiation on T2WI and FLAIR imaging. Long-term follow-up revealed a pattern of steady progression and a variety of clinical symptoms, including spastic paraplegia, peripheral neuropathy, reduced visual acuity, and some degree of cerebellar ataxia. Clinical variability between patients was observed to some extent, and therefore, further studies are required to determine the phenotype-genotype correlation.

A Case Series of Patients With MYBPC1 Gene Variants Featuring Undulating Tongue Movements as Myogenic Tremor.

Myosin-binding protein C1 (MYBPC1) encodes myosin-binding protein C, slow type (sMyBP-C), an accessory protein that regulates actomyosin cross-linking, stabilizes thick filaments, and modulates contractility in muscle sarcomeres and has recently been linked to myopathy with tremor. The clinical features of MYBPC1 mutations manifesting in early childhood bear some similarities to those of spinal muscular atrophy (SMA), such as hypotonia, involuntary movement of the tongue and limbs, and delayed motor development. The development of novel therapies for SMA has necessitated the importance of differentiating SMA from other diseases in the early infancy period. We report the characteristic tongue movements of MYBPC1 mutations, along with other clinical findings, such as positive deep tendon reflexes and normal peripheral nerve conduction velocity testing, which could help in considering other diseases as differential diagnoses.

A novel variant in the transmembrane 4 domain of ANO3 identified in a two-year-old girl with developmental delay and tremor.

ANO3 encodes Anoctamin-3, also known as TMEM16C, a calcium-activated chloride channel. Heterozygous variants of ANO3 can cause dystonia 24, an adult-onset focal dystonia. Some pediatric cases have been reported, but most patients were intellectually normal with some exceptions. Here, we report a two-year-old girl who showed mild to moderate developmental delay, tremor, and ataxic gait, but no obvious dystonia. Trio exome sequencing identified a heterozygous de novo missense variant NM_031418.4:c.1809T>G, p.(Asn603Lys) in the ANO3 gene. Three cases with ANO3 variants and intellectual disability have been reported, including the present case. These variants were predicted to face in the same direction on the same alpha-helix (the transmembrane 4 domain), suggesting an association between these variants and childhood-onset movement disorder with intellectual disability. In pediatric cases with developmental delay and movement disorders such as tremor and ataxia, specific variants in the transmembrane 4 domain of ANO3 may be a cause, even in the absence of dystonia.

Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation.

Mutations in the C-terminal region of the CDC42 gene cause severe neonatal-onset autoinflammation. Effectiveness of IL-1ß-blocking therapy indicates that the pathology involves abnormal inflammasome activation; however, the mechanism underlying autoinflammation remains to be elucidated. Using induced-pluripotent stem cells established from patients carrying CDC42R186C, we found that patient-derived cells secreted larger amounts of IL-1ß in response to pyrin-activating stimuli. Aberrant palmitoylation and localization of CDC42R186C protein to the Golgi apparatus promoted pyrin inflammasome assembly downstream of pyrin dephosphorylation. Aberrant subcellular localization was the common pathological feature shared by CDC42 C-terminal variants with inflammatory phenotypes, including CDC42*192C*24 that also localizes to the Golgi apparatus. Furthermore, the level of pyrin inflammasome overactivation paralleled that of mutant protein accumulation in the Golgi apparatus, but not that of the mutant GTPase activity. These results reveal an unexpected association between CDC42 subcellular localization and pyrin inflammasome activation that could pave the way for elucidating the mechanism of pyrin inflammasome formation.

Two types of early epileptic encephalopathy in a Pitt-Hopkins syndrome patient with a novel TCF4 mutation.

INTRODUCTION: Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by mutations in TCF4. Seizures have been found to vary among patients with PTHS. We report the case of a PTHS patient with a novel missense mutation in the gene TCF4, presenting with two types of early epileptic encephalopathy. CASE REPORT: The patient was a Japanese boy. His first seizure was reported at 17 days of age, with twitching of the left eyelid and tonic-clonic seizures on either side of his body. An ictal electroencephalogram (EEG) showed epileptic discharges arising independently from both hemispheres, occasionally resembling migrating partial seizures of infancy (MPSI) that migrated from one side to the other. Brain magnetic resonance imaging revealed agenesis of the corpus callosum. His facial characteristics included a distinctive upper lip and thickened helices. His seizures were refractory, and psychomotor development was severely delayed. At the age of 10 months, he developed West syndrome with spasms and hypsarrhythmia. After being prescribed topiramate (TPM), his seizures and EEG abnormalities dramatically improved. Also, psychomotor development progressed. Whole-exome sequencing revealed a novel de novo missense mutation in exon 18 (NM_001083962.2:c.1718A > T, p.(Asn573Ile)), corresponding to the basic region of the basic helix-loop-helix domain, which may be a causative gene for epileptic encephalopathy. CONCLUSIONS: To our knowledge, this is the first report of a patient with PTHS treated with TPM, who presented with both MPSI as well as West syndrome. This may help provide new insights regarding the phenotypes caused by mutations in TCF4.

The longest reported sibling survivors of a severe form of congenital myasthenic syndrome with the ALG14 pathogenic variant.

Congenital myasthenic syndromes (CMS) is a group of diseases that causes abnormalities at the neuromuscular junction owing to genetic anomalies. The pathogenic variant in ALG14 results in a severe pathological form of CMS causing end-plate acetylcholine receptor deficiency. Here, we report the cases of two siblings with CMS associated with a novel variant in ALG14. Immediately after birth, they showed hypotonia and multiple joint contractures with low Apgar scores. Ptosis, low-set ears, and high-arched palate were noted. Deep tendon reflexes were symmetrical. They showed worsening swallowing and respiratory problems; hence, nasal feeding and tracheotomy were performed. Cranial magnetic resonance imaging scans revealed delayed myelination and cerebral atrophy. Exome sequencing indicated that the siblings had novel compound heterozygous missense variants, c.590T>G (p.Val197Gly) and c.433G>A (p.Gly145Arg), in exon 4 of ALG14. Repetitive nerve stimulation test showed an abnormal decrease in compound muscle action potential. After treatment with pyridostigmine, the time off the respirator increased. Their epileptic seizures were well controlled by anti-epileptic drugs. Their clinical course is stable even now at the ages of 5 and 2 years, making them the longest reported survivors of a severe form of CMS with the ALG14 variant thus far.

Leigh syndrome-like MRI changes in a patient with biallelic HPDL variants treated with ketogenic diet.

Biallelic 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) variants were recently reported as a cause of progressive and incurable neurodegenerative diseases ranging from neonatal-onset leukoencephalopathy with severe neurodevelopmental delay to spastic paraplegia. Although the physiological function of HPDL remains unknown, its subcellular localization in the mitochondria has been reported. Here, we report a case of HPDL-related neurological disease that was clinically and neuroimaging compatible with Leigh syndrome, previously unreported, and was treated with a ketogenic diet.

Costello syndrome model mice with a HrasG12S/+ mutation are susceptible to develop house dust mite-induced atopic dermatitis.

Costello syndrome is an autosomal dominant disorder that is caused by germline HRAS mutations. Patients with Costello syndrome present craniofacial abnormalities, cardiac defects, and cancer predisposition, as well as skin abnormalities, including papillomas, keratosis pilaris, and eczematous dermatitis. However, the mechanisms underlying the dermatological abnormalities remain unclear. Here, we demonstrated that knock-in mice expressing an Hras G12S mutation (HrasG12S/+ mice) are susceptible to develop atopic dermatitis (AD)-like skin lesions, including eczema, pruritus, elevated serum IgE levels, acanthosis, and the infiltration of mast cells, basophils, and type-2 innate lymphoid cells in the dermis, after stimulation with house dust mite allergens (Dermatophagoides farinae, Dfb). Reduced skin barrier function, increased proliferation of phosphorylated ERK (p-ERK)-positive epidermal cells, and increased Th2-type cytokines as well as epithelial cell-derived cytokines, including IL-33, were observed in the skin tissue of HrasG12S/+ mice compared with Hras+/+ mice. Cultured HrasG12S/+ keratinocytes exhibited increased IL-33 expression after Dfb stimulation. PD0325901, an MEK inhibitor, ameliorated AD-like symptoms in HrasG12S/+ mice, showing decreased proliferation of p-ERK-positive epidermal cells and decreased expression of IL-33. Our findings indicate that the epidermis of HrasG12S/+ mice stimulated by Dfb strongly induced IL-33 expression and type-2 innate lymphoid cells, resulting in AD-like skin lesions. These results suggest that the epidermis of HrasG12S/+ mice are prone to development of eczematous dermatitis stimulated with house dust mite allergens.

Perinatal Coxsackievirus B3 Infection with Transient Thrombocytopenia.

Coxsackievirus (Cox) B is the second common picornaviruses, after echovirus, detected from children younger than 2 months of age. Neonates who present with Cox B3 infection in the first week are known to have severe illness such as myocarditis or menigoencephalitis. Severity is commonly associated with perinatal vertical transmission. Here, we report a neonatal case of Cox B3 infection with severe thrombocytopenia through horizontal transmission. The patient was a preterm infant born without asphyxia by selective cesarean section. From his 6(th) day of life, the patient had recurrent episodes of apnea. At that time, the laboratory investigations revealed a profound thrombocytopenia without any evidence of inflammation. Thus, neonatal alloimmune thrombocytopenia (NAIT) was suspected, and the patient received transfusion of immunoglobulin and platelets. Thereafter, the patient had no further episodes of apnea, and platelet counts of the patient increased gradually. Later, the possibility of NAIT was ruled out by the result of the platelet antigen genotyping of the patient and his parents. Culture obtained from his nasopharynx was positive for Cox B3. We thus speculate that the patient was exposed to the virus from his mother because she had a febrile episode at her 5(th) day after delivery, and her Cox B3 infection was confirmed by serology. Assuming that the thrombocytopenia was a complication of Cox B3 infection, the immunoglobulin transfusion might have provided a neutralizing antibody against Cox B3. It is important to consider the possibility of enterovirus infection as a differential diagnosis whenever unexplained thrombocytopenia was observed in neonates.

Somatic BRAF c.1799T>A p.V600E Mosaicism syndrome characterized by a linear syringocystadenoma papilliferum, anaplastic astrocytoma, and ocular abnormalities.

Genetic mosaicism for somatic mutations of oncogenes is common in genodermatoses, which can be complicated with extra-cutaneous abnormalities. Here we describe an infant with a congenital anaplastic astrocytoma, a linear syringocystadenoma papilliferum, and ocular abnormalities. The BRAF c.1799T>A p.V600E mutation was detected in both the brain and skin tumor cells but not in the blood or normal skin cells, suggesting somatic mosaicsism for the mutation. Clinically, the brain tumor gradually became life threatening without any response to conventional chemotherapies including carboplatin, etoposide, and temozolomide. Vemurafenib, a BRAF p.V600E inhibitor, was administered daily after the detection of the BRAF mutation. This single-agent therapy was dramatically effective against the anaplastic astrocytoma; the tumor regressed, the cerebrospinal fluid cell count and protein levels decreased to normal levels, and hydrocephalus resolved. Moreover, other lesions including a corneal cyst also responded to vemurafenib. The brain tumor continued shrinking after 6 months of treatment. We present a genodermatosis syndrome associated with BRAF c.1799T>A p.V600E mosaicism. This syndrome may represent a new entity in the mosaic RASopathies, partly overlapping with Schimmelpenning-Feuerstein-Mims syndrome, which is driven by mosaicism of HRAS and/or KRAS activating mutations. Screening for BRAF c.1799T>A p.V600E is especially useful for those with malignant tumors, because it is one of the most-druggable targets.

Novel missense mutation in CLN8 in late infantile neuronal ceroid lipofuscinosis: The first report of a CLN8 mutation in Japan.

Neuronal ceroid lipofuscinoses (NCLs) are clinically and genetically heterogeneous neurodegenerative lysosomal diseases. Fourteen distinct NCL subtypes (CLN1-CLN14) are known, and they are caused by mutations in different genes. CLN8 was first identified in Finnish patients, and the phenotype was subsequently found in Turkish, Italian, and Pakistani patients. We report a 6-year-old Japanese boy with NCL with a novel missense mutation in CLN8. At the age of 3years, he manifested frequent drop seizures, and then progressively developed motor difficulties with an ataxic gait, myoclonus, left conjugate deviation, and rotational nystagmus. At age 5, he developed profound visual difficulty and dysphagia, and he has now lost his mobility. A bone marrow examination at age 5 showed sea-blue histiocytes. An electroretinogram was non-recordable. No giant somatosensory evoked potentials were found. Brain magnetic resonance imaging revealed bilateral diffuse hyperintensities in the white matter around the lateral ventricles and cerebellar and pontine atrophy on T2-weighted images. In a lysosomal enzyme study, the palmitoyl-protein-thioesterase and pepinase activity was within normal limits. Whole-exome sequencing revealed a homozygous CLN8 mutation: c.620T>G (p.L207R). His parents were both heterozygous for this mutation. To our knowledge, this is the first report of a CLN8 mutation in late infantile NCL in Japan.

A case of acute cerebellitis with a unique sequential change on magnetic resonance imaging.

BACKGROUND: Acute cerebellitis with unilateral onset is rare, and magnetic resonance imaging (MRI) is a useful method for demonstrating cerebellar involvement. PATIENT: We report a 12-year-old girl with acute cerebellitis with a unique sequential change on her MRI. RESULTS: The patient's brain MRI first revealed cortical lesions mainly in the right cerebellar hemisphere. These subsequently disappeared, and at the same time, new lesions appeared in the opposite cerebellar hemisphere. All the lesions were confined to gray matter in the cerebellum and were isotense on diffusion-weighted imaging and had high signal intensity on the apparent diffusion coefficient map, consistent with the characteristic of vasogenic edema. CONCLUSION: The sequential MRI demonstrates conversion of hemicerebellitis to bilateral cerebellitis during subacute phase, and vasogenic edema might be contributing to the pathogenesis of acute cerebellitis in this patient.