neonatal hypotonia

Baker-Gordon Syndrome

Clinical Characteristics
Ocular Features: 

Poor visual acuity described as central in origin with poor eye contact.  Periorbital anomalies of low-set eyebrows and epicanthal folds are common.  The eyes have been described as "almond-shaped".  Strabismus and nystagmus are commonly present.

Systemic Features: 

The facial features ae described as "fine" with a short nose and a thin upper lip.  The forehead is unusually high. 

There is general developmental delay with impaired intellectual development, delayed or absent walking, and behavioral psychiatric manifestations such as stereotypic and unpredictable outbursts.   There are often involuntary and hyperkinetic movements with dystonia, dyskinesia, ataxia and choreoathetosis.  The EEG is often abnormal although seizures have not been reported.

Genetics

De novo heterozygous mutations in the SYT1 gene (12q21.2) have been associated with this condition.  

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

SYT1-associated neurodevelopmental disorder: a case series

Baker K, Gordon SL, Melland H, Bumbak F, Scott DJ, Jiang TJ, Owen D, Turner BJ, Boyd SG, Rossi M, Al-Raqad M, Elpeleg O, Peck D, Mancini GMS, Wilke M, Zollino M, Marangi G, Weigand H, Borggraefe I, Haack T, Stark Z, Sadedin S; Broad Center for Mendelian Genomics, Tan TY, Jiang Y, Gibbs RA, Ellingwood S, Amaral M, Kelley W, Kurian MA, Cousin MA, Raymond FL. SYT1-associated neurodevelopmental disorder: a case series. Brain. 2018 Sep 1;141(9):2576-2591.

PubMed ID: 
30107533

Spastic Paraplegia with Psychomotor Retardation and Seizures

Clinical Characteristics
Ocular Features: 

The eyes are usually deeply set.  Nothing is known regarding visual acuity.  Strabismus is a common feature.  Retinal dystrophy (not further described) has been reported in 4 of 8 patients described.  The ERG in one individual was read as consistent with cone-rod dystrophy.

Systemic Features: 

Newborns are hypotonic and severe psychomotor retardation is evident a few months later.  Truncal ataxia and progressive lower limb spasticity are seen later.  Mobility is significantly impaired and many individuals are confined to bed or a wheelchair and never walk.  Dysarthria is frequently present and some individuals have a neurosensory hearing loss.  Myoclonic seizures may be evident.  Kyphoscoliosis, macrocephaly, and various foot deformities have been described.

CT scans of the brain may show generalized cerebral atrophy and a hypoplastic corpus callosum.  The ventricles may be enlarged and the EEG confirms the occurrence of myoclonic as well as tonic-clonic and focal epilepsy.

Genetics

This is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the HACE1 gene (6q16).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for this condition but physical therapy and assistive devices such as hearing and visual aids may be helpful.

References
Article Title: 

DDD study. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families

Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M, Brady AF, Clayton S, Cole T, Deshpande C, Fitzgerald TW, Foulds N, Francis R, Gabriel G, Gerety SS, Goodship J, Hobson E, Jones WD, Joss S, King D, Klena N, Kumar A, Lees M, Lelliott C, Lord J, McMullan D, O'Regan M, Osio D, Piombo V, Prigmore E, Rajan D, Rosser E, Sifrim A, Smith A, Swaminathan GJ, Turnpenny P, Whitworth J, Wright CF, Firth HV, Barrett JC, Lo CW, FitzPatrick DR, Hurles ME; DDD study. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nat Genet. 2015 Nov;47(11):1363-9.

PubMed ID: 
26437029

HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome

Hollstein R, Parry DA, Nalbach L, Logan CV, Strom TM, Hartill VL, Carr IM, Korenke GC, Uppal S, Ahmed M, Wieland T, Markham AF, Bennett CP, Gillessen-Kaesbach G, Sheridan EG, Kaiser FJ, Bonthron DT. HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome. J Med Genet. 2015 Dec;52(12):797-803.

PubMed ID: 
26424145

Pontocerebellar Hypoplasia 3

Clinical Characteristics
Ocular Features: 

Optic atrophy is an inconsistent feature (sometimes even unilateral) of patients with PCH.  Cortical blindness has also been described.  There may be dysmorphic facial features such as wide palpebral fissures, epicanthal folds, and prominent eyes. 

Systemic Features: 

Infants are generally small and hypotonic at birth.  The skull is small and often brachycephalic.  The ears are large and low-set and  facial dysmorphism (full cheeks, long philtrum) is present.  Infants have poor head control and truncal ataxia.  Later, hyperreflexia and spasticity become evident.  Seizures are common.  Developmental delays, both somatic and mental, are nearly universal and large joint contractures are often seen. Many of these signs are progressive.  

Brain imaging generally reveals cerebral and cerebellar atrophy, a hypoplastic corpus callosum, a small cerebellar vermis, and a hypoplastic brainstem.  Short stature is a feature and early death often occurs.

Genetics

PCH3 is one of at least 10 syndromes belonging to a clinically and genetically heterogeneous group of conditions known as pontocerebellar hypoplasias.  Members of this group, while individually rare, nevertheless collectively account for a significant proportion of what was once labeled cerebral palsy.

PCH3 results from homozygous mutations in the PCLO gene (7q21). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the general disorder.

References
Article Title: 

Loss of PCLO function underlies pontocerebellar hypoplasia type III.

Ahmed MY, Chioza BA, Rajab A, Schmitz-Abe K, Al-Khayat A, Al-Turki S, Baple EL, Patton MA, Al-Memar AY, Hurles ME, Partlow JN, Hill RS, Evrony GD, Servattalab S, Markianos K, Walsh CA, Crosby AH, Mochida GH. Loss of PCLO function underlies pontocerebellar hypoplasia type III. Neurology. 2015 Apr 28;84(17):1745-50.

PubMed ID: 
25832664

Peroxisomol Fatty Acyl-CoA Reductase 1 Disorder

Clinical Characteristics
Ocular Features: 

At least some patients have cataracts which may be congenital in origin.  Highly arched eyebrows are part of the facial dysmorphism.

Systemic Features: 

Neonatal hypotonia is common while postnatal psychomotor development, somatic growth delay, microcephaly, and seizures become evident later.  The coarse facial dysmorphism includes large ears, a flattened nasal root, thin upper lip, a long philtrum, and a flattening of the nasal root.  Cognitive deficits are often present and some individuals have significant mobility problems. 

Red blood cell plasmalogen may be decreased.

Genetics

This condition results from homozygous or compound heterozygous mutations in FAR1 gene (11p15.2) resulting in complete loss of enzyme activity consistent with a defect in peroxisomes.

There is some clinical resemblance to rhizomelic chondrodysplasia punctata (215100) in which congenital cataracts also occur but lacks the skeletal features and results from a different mutation. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for the generalized condition but physical therapy and special education could be helpful.  Cataract removal is an option that may be considered.

References
Article Title: 
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