Baby M is a 3-day-old term neonate who presents with focal clonic seizures beginning on day 2 of life. Continuous EEG monitoring reveals a burst-suppression pattern — prolonged periods of voltage suppression interrupted by high-amplitude bursts of epileptiform activity. The birth history is reassuringly uncomplicated: spontaneous vaginal delivery at 39 weeks with APGAR scores of 8 at one minute and 9 at five minutes, ruling out significant perinatal hypoxic-ischemic injury. On examination, Baby M demonstrates axial hypotonia, poor feeding requiring nasogastric supplementation, and subtle distinctive features including a slightly broad nasal bridge and thin upper lip. Initial metabolic workup is unremarkable: glucose, electrolytes, lactate, and ammonia are all within normal limits, making acute metabolic decompensation unlikely. MRI of the brain shows no structural abnormality — no cortical malformation, no evidence of ischemic injury, and no white matter signal change. Chromosomal microarray returns normal, excluding aneuploidies and clinically significant copy number variants. The family history, however, provides important clues that must not be overlooked: the mother has a mild postural hand tremor that she has never investigated, and her maternal grandmother died of 'dementia' at age 55. The clinical team now faces a critical testing decision — whether to order a targeted epilepsy gene panel or proceed directly to rapid trio whole exome sequencing.

Rapid trio whole exome sequencing (Baby M plus both parents) returns within 10 days and identifies a de novo heterozygous pathogenic variant in KCNQ2: c.740C>T, p.Ala247Val. This missense variant is located in the S4 voltage sensor domain of the Kv7.2 potassium channel subunit and has been functionally characterized as a gain-of-function variant that causes increased channel opening and paradoxically enhanced neuronal excitability. The variant is reported in ClinVar as pathogenic by multiple independent submitters. ACMG classification is Pathogenic based on the following evidence codes: PS2 (confirmed de novo in a patient with the disease and no family history), PS3 (well-established functional studies demonstrate gain-of-function effect), PM1 (located in the critical S4 voltage sensor domain), PM2 (absent from population databases including gnomAD), and PP3 (multiple computational tools predict a deleterious effect). Based on the gain-of-function mechanism, carbamazepine — a sodium channel blocker — is initiated rather than conventional anticonvulsants. Seizures resolve completely within 48 hours, confirming the genotype-guided treatment approach. Separately, the mother's tremor and the grandmother's early-onset dementia prompt targeted FMR1 testing, which reveals that the mother carries an FMR1 premutation with 89 CGG repeats (normal <45, intermediate/gray zone 45–54, premutation 55–200). This explains the mother's tremor as early FXTAS and the grandmother's probable fragile X-associated tremor/ataxia syndrome. Baby M tests negative for FMR1 expansion. This case illustrates dual genetic findings within a single family — an increasingly recognized phenomenon in clinical neurogenetics.

Alex is a 14-year-old previously healthy teenager referred to the neurogenetics clinic with an 18-month history of progressive gait unsteadiness, frequent falls, and declining school performance. His parents first noticed difficulty during football practice when he began stumbling without apparent cause. Over the following months, his handwriting deteriorated and his speech became mildly slurred. Neurological examination reveals broad-based gait ataxia with inability to perform tandem walking, mild cerebellar dysarthria, and bilateral dysmetria on finger-to-nose testing. Deep tendon reflexes are absent at the knees and ankles bilaterally — a striking finding in a teenager with otherwise upper motor neuron signs. Vibration sense and proprioception are diminished in both feet, indicating posterior column involvement. Musculoskeletal examination demonstrates bilateral pes cavus (high-arched feet) and mild thoracolumbar scoliosis. Cardiac auscultation reveals a grade II/VI systolic murmur at the apex. MRI brain shows mild superior cerebellar vermis atrophy but no focal lesions, demyelination, or structural malformations. Family history is significant: Alex's parents are first cousins of Pakistani origin, and his older sibling, aged 17, has recently developed similar gait difficulties with frequent tripping. The consanguinity strongly suggests autosomal recessive inheritance, and the progressive ataxia differential must now be systematically evaluated.

Whole exome sequencing is ordered as the initial genetic test given the broad ataxia differential and consanguinity. The WES report returns negative — no pathogenic or likely pathogenic variants are identified in any known ataxia gene. However, the clinical team recognizes that WES cannot detect trinucleotide repeat expansions, and Alex's phenotype is highly suggestive of Friedreich ataxia. Targeted FXN GAA repeat analysis by repeat-primed PCR (RP-PCR) is ordered, and the result confirms the diagnosis: Alex is homozygous for GAA expansions with 850 and 920 repeats on the two alleles respectively (normal alleles contain fewer than 33 GAA repeats; premutation alleles 34–65; full mutation greater than 66). The diagnosis of Friedreich ataxia is confirmed. Echocardiography reveals concentric left ventricular hypertrophy consistent with early hypertrophic cardiomyopathy — the leading cause of premature death in Friedreich ataxia. Management is initiated with omaveloxolone (Skyclarys), the first FDA-approved therapy for Friedreich ataxia (approved February 2023). Omaveloxolone is an NRF2 pathway activator that reduces oxidative stress caused by frataxin deficiency and has demonstrated slowing of neurological decline in clinical trials. Cardiac surveillance with annual echocardiography and ECG is established. Physical therapy is prescribed for gait training and balance. Genetic counseling addresses autosomal recessive inheritance with 25% recurrence risk for future pregnancies. Alex's older sibling undergoes targeted FXN testing and is confirmed to carry the same homozygous GAA expansion — importantly, early treatment is initiated before significant cardiomyopathy develops, which may improve long-term cardiac outcomes.

Priya is a 5-year-old girl referred from the cerebral palsy clinic for genetic evaluation. She was diagnosed with spastic diplegic cerebral palsy at age 2 based on gross motor delay, increased tone in the lower extremities, and persistent toe-walking. Her birth history is unremarkable: she was born at term following an uncomplicated spontaneous vaginal delivery with normal APGAR scores, and there were no perinatal risk factors including no evidence of hypoxic-ischemic encephalopathy. The referring child neurologist has become concerned about several features inconsistent with the CP diagnosis. First, Priya's motor symptoms have been clearly progressive — she was able to walk independently with a posterior walker at age 3, but over the past 18 months her mobility has declined steadily, and she now requires a wheelchair for all distances. Second, her family reports a striking diurnal fluctuation pattern: Priya's tone and motor function are noticeably better in the morning after sleep and worsen progressively throughout the afternoon and evening. Third, MRI of the brain performed at age 2 was entirely normal with no evidence of periventricular leukomalacia, cortical malformation, or any structural lesion. Fourth, her older brother, aged 8, has mild persistent toe-walking but is otherwise functional with normal cognition and no formal diagnosis. The progressive course and diurnal fluctuation are fundamentally inconsistent with cerebral palsy, which is by definition a non-progressive motor disorder arising from a static brain lesion.

Based on the clinical suspicion for dopa-responsive dystonia, the neurology team initiates a therapeutic trial of low-dose levodopa/carbidopa at 1 mg/kg/day of levodopa. The response is dramatic and sustained: within two weeks, Priya demonstrates marked improvement in lower extremity tone and motor function. By one month, she is walking independently for the first time in over a year — a transformative clinical outcome. Genetic confirmation is obtained through sequencing of GCH1, which reveals a heterozygous pathogenic missense variant: c.607G>A, p.Val203Ile. This variant in GTP cyclohydrolase 1 disrupts the rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis, leading to deficiency of dopamine in the basal ganglia. ACMG classification is Pathogenic based on: PS3 (well-established in vitro functional studies demonstrate significantly reduced GTP cyclohydrolase 1 enzyme activity), PS4 (the variant has been reported in multiple unrelated families with dopa-responsive dystonia in the literature), PM2 (absent from gnomAD population database), PP1 (variant segregates with disease in the family — present in affected brother), and PP3 (computational tools uniformly predict deleterious effect). The combination of two Strong (PS3, PS4), one Moderate (PM2), and two Supporting (PP1, PP3) criteria meets the ACMG threshold for Pathogenic classification. Priya's 8-year-old brother undergoes targeted testing, is confirmed to carry the same GCH1 variant, and begins levodopa therapy with similar improvement in his toe-walking. GCH1-related dopa-responsive dystonia is autosomal dominant with incomplete penetrance, particularly in males — explaining the brother's milder presentation. This case powerfully illustrates why an estimated 20–30% of children with idiopathic cerebral palsy have an underlying genetic cause, and why treatable conditions such as dopa-responsive dystonia must never be missed. DRD is widely considered one of the most rewarding diagnoses in child neurology because of the dramatic and lifelong response to inexpensive, well-tolerated levodopa therapy. For detailed coverage of GCH1 and other genetic dystonias, see the Genetic Dystonias module.