Table 4 Genetic, clinical, and neuroimaging findings of previously reported PCH cases with genes involved in other underlying etiologies

PCH1A

AR

VRK1

Prenatally or at birth

Microcephaly

Respiratory insufficiency

Poor feeding

NR

Congenital contractures, Foot deformities, Muscle weakness, Fasciculations, Hypotonia

Psychomotor retardation, Mental retardation, Ataxia, Hyperreflexia

NR

NR

Spinal cord anterior horn cell degeneration, Pontocerebellar hypoplasia, Hypoplasia of the ventral pons, Neuronal loss in the brainstem, Neuronal loss in basal ganglia, Gliosis in the brainstem, Gliosis in the basal ganglia,

NR

Death in childhood may occur

12548734, 19646678, 8147499

PCH1E

AR

SLC25A46

at birth

Dysmorphic facial features (Exotropia, Bitemporal narrowing, Upturned nose with bulbous tip, tented upper lip, narrow palate, flat midface), Optic atrophy, Progressive visual impairment, Nystagmus, Rod-cone dysfunction

Respiratory failure

NR

NR

Scoliosis, Pes cavus, Contacture, Hypotonia, Dysarthria, Neurogenic atrophy, Tapered fingers

Developmental delay, Lack of spontaneous movement, No developmental skills acquired, Ataxic gait, Seizures, Sensorimotor neuropathy

NR

NR

Pontocerebellar hypoplasia, Cerebellar atrophy, Mild atrophy of the brainstem, loss of spinal motor neurons

Increased serum lactate

Polyhydramnios (prenatal), Death may occure in the first days or weeks of life

8147499, 27543974, 27390132, 28653766, 26168012, 27543974, 28558379, 28653766, 36578309

PCH2E

AR

VPS53

in infancy

Progressive microcephaly, Dysmorphic facial features (Bitemporal narrowing, Micrognathia, Prominent earlobes, Epicanthal folds, Strabismus, Short wide nose,) Poor or absent visual tracking, Optic atrophy, Gaze-evoked nystagmus

NR

NR

NR

Hypotonia, Distal limb edema, Joint contractures, Osteoporosis, Scoliosis

Delayed psychomotor development, Lack of developmental milestones, Mental retardation, Absent speech, Irritability, Seizures, Poor spontaneous movement, Progressive spastic quadriplegia, Opisthotonus, Spasticity

NR

NR

Progressive cerebellar atrophy, Progressive cerebral atrophy, Thin corpus callosum

NR

Short stature, Failure to thrive, Poor overall growth, Progressive disorder

24577744, 12920088, 30100179

PCH3

AR

PCLO

at birth

Microcephaly, Brachycephaly, Dysmorphic facial features (Long philtrum, Full cheeks, Low-set ears, Large ears, Prominent eyes, Wide palpebral fissures, Depressed nasal bridge, High arched mouth palate), Hearing impairment, Optic atrophy

NR

NR

NR

NR

Developmental delay, Neonatal hypotonia, Poor head control, Seizures, Hyperreflexia, Truncal hypotonia, Spasticity

NR

NR

Small brainstem, Small cerebellum, Cerebral atrophy, Hypoplasia of the corpus callosum,

NR

Short stature, Low weight, Progressive disorder

19277761

PCH8

AR

CHMP1A

at birth

Microcephaly, Dysmorphic features, Myopia, Astigmatism, Esotropia, Strabismus, Hyperopia, Nystagmus, Cortical visual impairment, Poor visual tracking

NR

Gastroesophageal reflux, Swallowing difficulties

NR

Hypotonia, Joint contractures, Arthrogryposis, Claw feet, Pes cavus, Equinovarus, Talipes valgus

Delayed psychomotor development, Mental retardation, Poor speech, Lack of speech, Lack of independent walking, Truncal hypotonia, Spasticity, Hyperreflexia, Choreiform movements

NR

NR

Cerebellar hypoplasia, Relative preservation of the cerebellar folia, Brainstem hypoplasia, Reduced cerebral white matter, Thin corpus callosum

NR

Poor postnatal growth

23023333, 36694001

PCH9

AR

AMPD2

at birth or in early infancy

Progressive microcephaly, Optic atrophy, Cortical blindness, Poor eye fixation, Nystagmus, Strabismus,

NR

NR

NR

NR

Delayed psychomotor development, Absent development, Axial hypotonia, Spasticity, Clonus, Hyperreflexia, Seizures

NR

NR

Pontocerebellar hypoplasia, Thin corpus callosum, Fluid filled posterior fossa, Cerebral cortical atrophy, “Figure 8” appearance of midbrain, Ventricular dilatation, Hypomyelination

NR

NR

23911318, 27066553, 29463858

PCH11

AR

TBC1D23

in early infancy

Microcephaly, Dysmorphic features (Large ears, Strabismus, Esotropia, Hyperopia, Bulbous nasal tip), Poor eye contact, Coloboma, Prominent incisors teeth

Recurrent respiratory infections

Dysphagia

NR

Hypotonia, Muscle atrophy, Talipes equinovarus

Delayed psychomotor development, Intellectual disability, Language delay, Difficulty walking, Cerebellar ataxia, Inability to walk, Wide-based gait, Dysarthria, Poor coordination, Limb ataxia, hyporeflexia of the lower extremities, Spasticity, Seizures

Happy demeanor, Autistic features, Stereotypic behavior, Attention deficit-hyperactivity, Aggressive and auto-aggressive behavior

NR

Hypoplastic corpus callosum, Cortical hypoplasia, Cerebellar atrophy

NR

Short stature, Low weight, Poor overall growth,

28823706, 28823707, 36076253, 32360255

PCH12

AR

COASY

in utero

Microcephaly, Sloping forehead, Micrognathia

NR

poor sucking

NR

Contractures, Arthrogryposis

Seizures, Spasticity

NR

NR

Cerebellar hypoplasia, Brainstem hypoplasia, Spinal cord hypoplasia, Small cerebrum, Corpus callosum agenesis, Simplified gyral pattern, Optic neuropathy

NR

Polyhydramnios, Death in infancy

30089828, 35499143, 32410094

PCH13

AR

VPS51

in infancy

Microcephaly,Brachycephaly, Dysmorphic facial features (Hypotonic facies, Full cheeks, Short philtrum, Overfolded ears, Epicanthal folds, Strabismus, Ptosis, Long eyelashes, Nystagmus, Hypertelorism, Upturned nasal tip, Thin upper lip, Thick vermilion of the upper lip, Narrow palate, High-arched palate), Cortical visual impairment, Dental caries

Recurrent respiratory infections, Sleep apnea, Asthma

Feeding difficulties, Tube feeding, Constipation, Cholestatic hepatitis, Hepatomegaly, Hepatic dysfunction

NR

Hypotonia, Lower extremity edema, Pes planus

Global developmental delay, Impaired intellectual development, Absent speech, Inability to sit or walk, Delayed walking, Ataxic gait, Seizures

NR

NR

Cerebellar atrophy, Thin corpus callosum, Cerebral atrophy, Dandy-Walker variant, Periventricular white matter abnormalities, Reduced white matter volume

Abnormal liver enzymes, Hypoglycosylation of serum transferrin

Failure to thrive, Poor overall growth

30624672, 31207318

PCH16

AR

MINPP1

at birth

Progressive microcephaly, Micrognathia, Low-sets ears, Prominent nose, Nystagmus, Ptosis, Optic atrophy, Cataracts, Abnormal ocular movements, Blindness

NR

Dysphagia, Tube feeding

NR

Scoliosis

Lack of developmental milestones, Lack of independent walking, Delayed motor development, Impaired intellectual development, Poor or absent speech, Poor social interaction, Seizures, Hypotonia (axial), Hypertonia (limb), Spastic tetraplegia, Stereotypic movements, Extrapyramidal signs, Ataxia, Stiffness, Spasticity

NR

NR

Pontocerebellar hypoplasia, Basal ganglia hypoplasia, Thalamic hypoplasia, Thin corpus callosum, Cerebral cortical atrophy

NR

NR

33257696, 33168985

PCH17

AR

PRDM13

in utero

Microcephaly, Dysmorphic facial features, Visual defects, Cleft palate

Respiratory insufficiency, Apnea, Hypoventilation

Feeding difficulties, Swallowing difficulties, Tube feeding

NR

NR

NR

Neonatal hypotonia, Absent developmental progress, Global developmental delay, Impaired intellectual development, Distal hypertonia, Spastic tetraplegia, Seizures, Autonomic dysfunction

NR

Cerebellar hypoplasia, Brainstem hypoplasia

Hypoglycemia

Poor overall growth, Bradycardia, Hypertension

35390279