FOXP2-related speech and language disorder (FOXP2-SLD) is caused by heterozygous FOXP2 pathogenic variants (including whole- or partial-gene deletions). The core phenotype of FOXP2-SLD is childhood apraxia of speech (CAS), a disorder of speech motor programming or planning that affects the production, sequencing, timing, and stress of sounds, and the accurate sequencing of speech sounds into syllables and syllables into words. CAS also interferes nonselectively with multiple other aspects of language, including phonology, grammar, and literacy. Additional findings in FOXP2-SLD can include oral-motor dyspraxia (difficulty planning or programming oral movements on command); dysarthria; moderate-to-severe receptive and expressive language disorder; reading and spelling impairments; and fine motor difficulties. Nonverbal (performance) IQ is typically relatively preserved compared to verbal IQ; gross motor skills are normal. Autistic features or a diagnosis of autism spectrum disorder have been reported in some individuals.

Biotin-thiamine-responsive basal ganglia disease (BTBGD) may present in early infancy, childhood, or adulthood. Early-infantile BTBGD presents before age three months with vomiting, feeding difficulties, encephalopathy, hypotonia, seizures, and respiratory failure. Classic BTBGD presents between ages three and ten years with recurrent subacute encephalopathy manifesting as confusion, seizures, ataxia, supranuclear facial palsy, external ophthalmoplegia, and/or dysphagia that, if left untreated, can eventually lead to coma and even death. Dystonia and cogwheel rigidity are nearly always present; hyperreflexia, ankle clonus, and Babinski responses are common. Hemiparesis or quadriparesis may be seen. Episodes are often triggered by febrile illness or mild trauma or stress. Simple partial or generalized seizures are easily controlled with anti-seizure medication. Adult Wernicke-like encephalopathy BTBGD, described in three individuals to date, presents after age ten years with acute onset of status epilepticus, ataxia, nystagmus, diplopia, and ophthalmoplegia. Prompt administration of biotin and thiamine early in the disease course results in partial or complete improvement within days in classic and adult BTBGD; however, most infants with early-infantile BTBGD have a poor outcome.

SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) is characterized by onset of the following features in infancy: developmental delay, hypotonia, dystonia, muscular atrophy, sensorineural hearing impairment, growth failure, and feeding difficulties. Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis. The median survival is age 20 years; approximately 30% of affected individuals succumb during childhood.

TK2-related mitochondrial DNA (mtDNA) maintenance defect is a phenotypic continuum that ranges from severe to mild. To date, approximately 107 individuals with a molecularly confirmed diagnosis have been reported. Three main subtypes of presentation have been described: Infantile-onset myopathy with neurologic involvement and rapid progression to early death. Affected individuals experience progressive muscle weakness leading to respiratory failure. Some individuals develop dysarthria, dysphagia, and/or hearing loss. Cognitive function is typically spared. Juvenile/childhood onset with generalized proximal weakness and survival to at least 13 years. Late-/adult-onset myopathy with facial and limb weakness and mtDNA deletions. Some affected individuals develop respiratory insufficiency, chronic progressive external ophthalmoplegia, dysphagia, and dysarthria.

Combined oxidative phosphorylation deficiency-6 (COXPD6) is an X-linked recessive severe encephalomyopathic disorder with onset in utero or in infancy. Affected patients have hypotonia and severely impaired psychomotor development associated with variably decreased enzymatic activity of mitochondrial respiratory complexes in skeletal muscle or fibroblasts. More variable features may include sensorimotor neuropathy, seizures, severe muscle weakness, abnormal signals in the basal ganglia, hypertrophic cardiomyopathy, deafness, swallowing difficulties, and respiratory insufficiency. Death in childhood may occur (summary by Berger et al., 2011). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Diencephalic-mesencephalic junction dysplasia syndrome-2 (DMJDS2) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay and hypotonia apparent from infancy. Affected individuals develop severe progressive hyperkinetic movements, including spastic tetraplegia, dystonia, and bulbar dysphagia necessitating tube feeding. Patients are unable to walk and have severely impaired intellectual development with absent speech. Brain imaging shows a unique malformation reflecting abnormal embryonic development of the diencephalic-mesencephalic junction (DMJ), with agenesis of the basal ganglia and olfactory bulb, hypoplasia of the thalamus, and abnormal course of the corticospinal tracts (summary by De Mori et al., 2019). For a discussion of genetic heterogeneity of DMJDS, see DMJDS1 (251280).