The proband, a 13-year-old boy, presented at our outpatient clinic with unexplained developmental delays and cognitive impairment. He was delivered at 40 weeks via cesarean section, a decision influenced by a previous cesarean, and had a birth weight of 2,800 g. His older brother had a history of acute lymphocytic leukemia, but there were no other significant medical histories related to development. During the neonatal period, he experienced feeding difficulties and hypotonia. Since birth, he has had microcephaly and small genitalia, along with short stature. A clinical examination revealed facial dysmorphism, characterized by downslanting palpebral fissures, pronounced eyebrows, a broad nasal bridge, enlarged and anteverted nostrils, crowded dentition, a long philtrum, round cheeks, pursed lips, and micrognathia (Fig. 1A). He also presented with camptodactyly of all fingers, adducted thumbs, fixed ulnar deviation, flexion contractures in both hands, limb tremors, and marked hyperhidrosis (Fig. 1B). The patient began walking at 36 months and exhibited global developmental delays and intellectual disability. Neurological assessment showed hypotonia in the extremities, coordination difficulties, and gait ataxia. All biomedical and metabolic studies, including tandem mass spectrometry, thyroid function tests, and tests for serum lactic acid/pyruvic acid, serum amino acids, ammonia, creatine kinase, urine glycosaminoglycans, and urine organic acids, were within normal limits. Peripheral blood karyotype, chromosomal microarray analysis, methylation polymerase chain reaction for Prader-Willi syndrome, and the fragile X messenger ribonucleoprotein 1 (FMR1) DNA test for fragile X syndrome all yielded normal results. Additionally, brain magnetic resonance imaging performed at 6 years of age showed diffuse cerebellar atrophy. Electroencephalography revealed slow and disorganized background cerebral activity and frequent sharp waves over both frontal areas, although the patient never experienced an unprovoked seizure. Genomic DNA was extracted from a buccal swab sample from the patient. Whole-exome sequencing (WES) was conducted using SureSelect Human All Exon V6 (Agilent, Santa Clara, CA, USA) and the NovaSeq platform (Illumina, San Diego, CA, USA). Sequence reads were aligned to the reference genome (The University of California, Santa Cruz Genome Browser, assembly hg19) using Burrows-Wheeler aligner (v.0.7.12, maximal exact matches algorithm), and the mean depth of coverage was 100× (>10×=99.2%). The heterozygous missense variant c.3553G>A, p.Ala1185Thr in NALCN was identified in WES. In silico tool predictions suggested that this variant had a damaging effect on the gene or gene product. Sanger sequencing was performed for the proband and his parents, identifying the variant as de novo (Fig. 2). The variant was categorized as ‘likely pathogenic’ based on the American College Medical Genetics and Genomics guidelines (PS2, PM2, and PP3) [5]. The patient is currently 18 years old, and motor symptoms such as postural instability, tremor, stiffness, and frozen gait began to appear around the age of 11-12. He initially trembled when nervous, but the duration of tremors increased over time. He experiences uncontrolled tremors and severe diaphoresis, for which he is being treated with propranolol. The tremors have shown only slight improvement, and he continues to receive rehabilitation therapy and symptomatic treatment.

NALCN is a conserved voltage-gated cation channel permeated to Na⁺ and Ca²⁺ ions [1,6]. The gene encoding NALCN is located on chromosome 13q33.1. Studies in mice have demonstrated that both loss-of-function and gain-of-function mutations in NALCN can have significant consequences [6]. A null mutation in NALCN can cause membrane hyperpolarization in neurons and disrupt periodic behaviors such as breathing, circadian rhythms, or rhythmic motor circuits [6]. Patients with symptoms of hypotonia, developmental delay, and abnormal NALCN channels should be evaluated for infantile hypotonia with psychomotor retardation and characteristic facies type 1 (IHPRF1; #615419). It is caused by loss-of-function, homozygous, or compound heterozygous mutations in NALCN. Affected individuals show very poor cognitive development and characteristic faces with onset at birth or in early infancy [7]. Heterozygous gain-of-function mutations in NALCN cause CLIFAHHD. It was previously hypothesized that the dominant negative protein can cause a loss-of-function phenotype, but overexpression of a mutant ortholog in Caenorhabditis elegans led to dominant channelopathy caused by a gain-of-function mutation in NALCN [6]. CLIFAHDD syndrome was first reported by Chong et al. [4] and typically manifests with a dysmorphic face, arthrogryposis, joint contractures, hypotonia, and global developmental delay. Here, we report typical CLIFAHDD symptoms in an 18-year-old male patient with a NALCN variant. The patient also has Parkinson’s syndrome with tremor, bradykinesia, poor coordination and balance, and stiffness, which, to our knowledge, have been rarely reported in adolescents. Recent studies have reported an association between NALCN and Parkinson’s disease, as well as psychiatric symptoms [8]. NALCN has been implicated in dystonia, regulation of movement, cognitive impairment, sleep, and circadian rhythms. It regulates major processes that are adversely affected in Parkinson’s disease, including the resting membrane potential, pace-making activities, and synaptic vesicle recycling [8]. In particular, the loss of NALCN, which is expressed in dopaminergic neurons, alters the ion balance of neurons, leading to high K⁺ levels and low Ca⁺⁺ levels, especially at gap junctions. This imbalance makes the depolarization of motor neurons or upstream interneurons difficult, resulting in relative hyperpolarization during repolarization, which can explain freezing and uncontrolled spontaneous movement [9,10]. Our patient adds to the body of known evidence regarding patients with CLIFAHDD syndrome and parkinsonism in adolescence, providing additional information on patients with this rare condition. Further research and the identification of more patients are needed to establish the genotype-phenotype correlation, predict the disease course, and develop appropriate treatment strategies. In particular, it is necessary to study what interventions are necessary for parkinsonism symptoms in patients with CLIFAHDD, what other psychiatric symptoms may occur with age, and how these can be controlled.

This study was approved by the Institutional Review Board of the Pusan National University Hospital, Pusan National University School of Medicine (2411-012-145). Informed consent was obtained from the parents. The patients’ medical records and other data were anonymized to ensure confidentiality.