Hong Li

X‐linked adrenoleukodystrophy (X‐ALD) is a peroxisomal disorder caused by pathogenic variants in ABCD1 , resulting in the accumulation of very long‐chain fatty acids and risk of progressive neuroinflammatory demyelination in the cerebral form of ALD. Brain MRI is the current standard neuroimaging modality for diagnosis and monitoring of central nervous system involvement. However, MRI primarily detects structural abnormalities and may not fully reflect functional impairment, neuroinflammatory activity, or early cerebral involvement. Positron emission tomography (PET) may provide complementary information beyond conventional MRI. Therefore, we aimed to review the current literature on PET imaging in X‐ALD. A systematic literature search was conducted in accordance with PRISMA guidelines using MEDLINE and Embase databases up to April 26, 2026. Studies evaluating brain PET imaging in individuals with X‐ALD were included. Data on study design, phenotype, ABCD1 genotype, brain MRI findings, PET tracers, analytic methods, and key findings were extracted. A total of 48 records were screened, resulting in the inclusion of 10 case reports and one case series comprising 12 patients. PET tracers included ¹⁸ F‐fluorodeoxyglucose (FDG) ( N = 19 patients), ¹¹ C‐(R)‐PK11195 ( N = 1), and L‐[methyl‐ ¹¹ C]methionine ( N = 1). One additional patient underwent PET assessment of cerebral blood flow and oxygen metabolism using unspecified tracers. In FDG‐PET studies, cortical hypermetabolism was reported in 12/19 individuals, whereas cortical hypometabolism was observed in 18/19 individuals, with findings in one case being either not specified or inconclusive. FDG‐PET demonstrated cortical glucose hypometabolism overlying the affected white matter (WM) in 6/18 individuals with T2 and/or FLAIR‐hyperintense WM lesions on MRI. FDG‐PET demonstrated cortical glucose hypometabolism in 12/18 individuals without WM lesions on MRI. The FDG‐PET findings were reported to correlate with clinical symptoms. Neuroinflammation‐targeted ¹¹ C‐(R)‐PK11195 PET demonstrated increased tracer binding in active WM lesions. Similarly, protein synthesis‐targeted L‐[methyl‐ ¹¹ C]methionine PET demonstrated increased tracer uptake in active WM lesions. PET may detect functional and neuroinflammatory abnormalities beyond those identified by structural MRI in individuals with X‐ALD, suggesting a potential role in evaluating the extent and severity of brain involvement. However, the available evidence is limited by small sample sizes, underrepresentation of pediatric and presymptomatic cases, heterogeneous PET tracers and analytic methodologies, and a lack of longitudinal data. Further multimodal and longitudinal studies are needed to establish the clinical utility of PET as a surveillance tool in X‐ALD.

Background: CLTC-related neurodevelopmental disorder is a rare condition primarily characterized by global developmental delay (GDD) and intellectual disability (ID). To date, approximately 41 cases involving CLTC gene alterations have been reported. We present the first individual with a complete deletion of the CLTC gene. Methods: The proband is a male from a non-consanguineous family, presenting with congenital nystagmus, hypotonia, GDD, and autism spectrum disorder (ASD). Chromosomal microarray analysis and trio exome sequencing were performed. A systematic review of previously reported CLTC variant cases was conducted to delineate the phenotypic spectrum. Results: A de novo 363-kb heterozygous deletion at 17q23.1 spanning the entire CLTC gene was identified. The systematic review confirmed GDD/ID as core features and revealed various ocular abnormalities in a subset of cases. These findings indicate that the clinical phenotype extends beyond neurodevelopment, with multi-system involvement. Conclusions: The phenotypic heterogeneity of CLTC-related disorders underscores the need for comprehensive physical examination to identify extra-neurological manifestations. Accurate diagnosis relies on integrating detailed clinical phenotyping with comprehensive genomic testing. Early, precise diagnosis facilitates multidisciplinary management, informed genetic counseling, and the establishment of long-term surveillance protocols.

Phenylketonuria (PKU) is associated with neurocognitive and neuropsychological symptoms despite early treatment and well‐controlled phenylalanine (Phe) levels. PKU impairs the conversion of Phe to tyrosine and causes excess phenylalanine to accumulate. This accumulation can competitively block some other amino acids from entering the brain. This may reduce production of key neurotransmitters like dopamine and serotonin, which can affect brain function and development. However, direct correlations between blood Phe levels and central nervous system (CNS) neurotransmitter concentrations have not been established, and reliable CNS biomarkers are lacking. Positron emission tomography (PET) enables in vivo assessment of brain metabolism and neurotransmitter‐related processes; therefore, we aim to investigate its potential value as a biomarker. A systematic literature search was conducted in accordance with PRISMA guidelines using MEDLINE and Embase databases up to April 25, 2026. Studies evaluating brain PET imaging in individuals with PKU or hyperphenylalaninemia were included. Data on study design, patient characteristics, PET tracers, and key findings were extracted and synthesized qualitatively. A total of 380 records were screened, and 13 studies were included, with a mean sample size of 8.8 (median 6). PET tracers included ¹⁸ fluorodeoxyglucose (FDG), amino acids, including tyrosine‐, methionine‐, leucine‐, aminocyclohexanecarboxylate‐based tracers, and fluorodopa‐related tracers. FDG PET studies demonstrated regionally heterogeneous abnormalities in brain glucose metabolism, independent of plasma Phe levels. Amino acid PET studies demonstrated reduced cerebral protein synthesis associated with impaired large neutral amino acid transport and increased brain Phe levels. Fluorodopa‐related PET studies indicated reduced dopaminergic activity, with no significant correlation between plasma Phe levels and striatal fluorodopa utilization. PET is a promising tool to bridge the gap between peripheral biochemical markers and CNS dysfunction in PKU. Further studies are needed to overcome limitations which include small sample sizes, heterogeneous metabolic control, restricted availability of tracer types, predominantly cross‐sectional study designs, and lack of correlation with clinical signs and symptoms.

We report on two patients with four‐limb postaxial polydactyly and a recurrent de novo missense variant (c.179G>A) in the MAX gene. This variant has been previously reported in four other cases of polydactyly, progressive macrocephaly, and ophthalmologic abnormalities. Our two cases represent the fifth and sixth known occurrences of this apparently rare genetic disorder. In addition to the previously reported findings, our patients exhibit novel clinical features, including orofacial clefting, congenital heart defects (coarctation of the aorta, secundum atrial septal defect), natal teeth, and sacrococcygeal teratoma. The present study emphasizes the importance of genetic testing in patients presenting with polydactyly and associated anomalies. These cases support the pathogenicity of the recurrent MAX c.179G>A (p.Arg60Gln) variant and significantly broaden the phenotypic spectrum of polydactyly–macrocephaly syndrome/MAX‐related disorder.

Classic homocystinuria (HCU) is caused by a deficiency in cystathionine beta‐synthase, leading to excessive accumulation of homocysteine and methionine in plasma and tissues. Clinical manifestations typically involve the eyes, skeleton, central nervous system, and vasculature. Thromboembolic events, such as stroke and deep vein thrombosis, are well‐recognized complications. Here, we report four patients with poorly controlled HCU who developed acute pancreatitis (AP) with varying outcomes, along with 11 additional cases identified through a literature review. This study highlights AP as a potential complication in poorly controlled HCU, expanding the clinical spectrum of the disease and offering guidance on surveillance and appropriate acute management.

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals’ family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants.

Monoallelic variants of CTCF cause an autosomal dominant neurodevelopmental disorder with a wide range of features, including impacts on the brain, growth, and craniofacial development. A growing number of subjects with CTCF‐related disorder (CRD) have been identified due to the increased application of exome sequencing, and further delineation of the clinical spectrum of CRD is needed. Here, we examined the clinical features, including facial profiles, and genotypic spectrum of 107 subjects with identified CTCF variants, including 43 new and 64 previously described subjects. Among the 43 new subjects, 23 novel variants were reported. The cardinal clinical features in subjects with CRD included intellectual disability/developmental delay (91%) with speech delay (65%), motor delay (53%), feeding difficulties/failure to thrive (66%), ocular abnormalities (56%), musculoskeletal anomalies (53%), and behavioral problems (52%). Other congenital anomalies were also reported, but none of them were common. Our findings expanded the genotypic and phenotypic spectrum of CRD that will guide genetic counseling, management, and surveillance care for patients with CRD. Additionally, a newly built facial gestalt on the Face2Gene tool will facilitate prompt recognition of CRD by physicians and shorten a patient's diagnostic odyssey.

Elevated total plasma homocysteine (hyperhomocysteinemia) is a marker of cardiovascular, thrombotic, and neuropsychological disease. It has multiple causes, including the common nutritional vitamin B12 or folate deficiency. However, some rare but treatable, inborn errors of metabolism (IEM) characterized by hyperhomocysteinemia can be missed due to variable presentations and the lack of awareness. The aim of this study is to identify undiagnosed IEM in adults with significantly elevated homocysteine using key existing clinical data points, then IEM specific treatment can be offered to improve outcome. We conducted a retrospective study with data mining and chart review of patients with plasma total homocysteine >30 μmol/L over a two‐year period. We offer biochemical and genetic testing to patients with significant hyperhomocysteinemia without a clear explanation to diagnose IEM. We identified 22 subjects with significant hyperhomocysteinemia but no clear explanation. Subsequently, we offered genetic testing to seven patients and diagnosed one patient with classic homocystinuria due to cystathionine beta‐synthase deficiency. With treatment, she lowered her plasma homocysteine and improved her health. This study stresses the importance of a thorough investigation of hyperhomocysteinemia in adults to identify rare but treatable IEM. We propose a metabolic evaluation algorithm for elevated homocysteine levels.

D‐2‐hydroxyglutaric aciduria (D‐2‐HGA) is a rare neurometabolic disease with two main subtypes, caused by either inactivating variants in D2HGDH (type I) or germline gain of function variants in IDH2 (type II), that result in accumulation of the same toxic metabolite, D‐2‐hydroxyglutarate. The main clinical features of both are neurologic, including developmental delay, hypotonia, and seizures. Dilated cardiomyopathy is a unique feature thus far only reported in type II. As somatic variants in IDH2 are frequently identified in several different types of cancer, including acute myeloid leukemia (AML), a link between cancer and this metabolic disease has been proposed; however, there is no reported cancer in patients with either type of D‐2‐HGA. Murine models have demonstrated how D‐2‐hydroxyglutarate alters metabolism and epigenetics, a potential mechanism by which this metabolite may cause cancer and cardiomyopathy. Here, we report the first case of both AML and dilated cardiomyopathy in a pediatric patient with D‐2‐HGA type I, who was treated with an anthracycline‐free regimen. This report may expand the clinical spectrum of this rare metabolic disease and provide insight on long‐term surveillance and care. However, this case is complicated by the presence of a complex chromosomal rearrangement resulting in a 25.5 Mb duplication of 1q41 and a 2.38 Mb deletion of 2q37.3. Thus, the direct causal relationship between D‐2‐HGA and leukemogenesis or cardiomyopathy warrants further scrutiny.

Congenital hyperinsulinism (CHI) is genetically heterogeneous, caused by pathogenic variants in multiple known genes regulating insulin secretion from the pancreatic β‐cells. The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1), a key player in insulin secretion, and pathogenic variants in ABCC8 are the most common cause of CHI. With increased application of genetic testing in clinical practice, variants of unknown clinical significance (VUS) are commonly reported. Additional functional investigation for variant pathogenicity is fundamental in establishing definitive molecular diagnosis and in guiding clinical management. However, due to the lack of ubiquitous tissue expression of these genes, obtaining functional studies on affected tissue has been challenging. We present a case of severe congenital hyperinsulinism which required a near‐total pancreatectomy. CHI gene sequencing identified a homozygous silent variant in ABCC8 located on the last nucleotide of exon 38, c.4608G>A (p.Ala1536Ala). The total RNA was isolated from pancreas resected at the time of pancreatectomy. RNA sequencing and expression analysis demonstrated exon 38 skipping and decreased RNA expression, which supports the pathogenicity of this variant. This case highlights the feasibility of functional studies of VUS on resected pancreatic tissue. The result expands the mutation spectrum in ABCC8 and allows precise genetic counseling to affected families.