progressive microcephaly

Neurodevelopmental Disorder with Progressive Microcephaly, Spasticity, and Brain Anomalies

Clinical Characteristics
Ocular Features: 

 Examined patients have optic atrophy with nystagmus and roving eye movements.

Systemic Features: 

There are extensive and, in most cases, progressive CNS abnormalities resulting in severe neurodevelopmental deficits.  Infants at birth have progressive truncal hypotonia and limb spasticity.  Motor deficits result in little spontaneous movement, resulting in poor sucking, and respiratory difficulties.  Language does not develop and there is profound mental retardation. Progressive microcephaly is a characteristic finding.  There are often extrapyramidal signs such as rigidity and dystonic posturing.

Dysmorphic features include a short nose, high-arched palate, low-set and posteriorly rotated ears, micrognathia, postaxial polydactyly, hirsutism, pectus carinatum, contractures of large joints, and hyperextensibility of small joints.

Brain imaging shows a progressive leukoencephalopathy, cerebral and cerebellar atrophy, and delayed myelination.  The corpus callosum is often thin and the ventricles appear enlarged.  The lifespan is generally short with death occurring in infancy or early childhood.

Genetics

This autosomal recessive disorder results from homozygous mutations in the PLAA gene (9p21). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins

Hall EA, Nahorski MS, Murray LM, Shaheen R, Perkins E, Dissanayake KN, Kristaryanto Y, Jones RA, Vogt J, Rivagorda M, Handley MT, Mali GR, Quidwai T, Soares DC, Keighren MA, McKie L, Mort RL, Gammoh N, Garcia-Munoz A, Davey T, Vermeren M, Walsh D, Budd P, Aligianis IA, Faqeih E, Quigley AJ, Jackson IJ, Kulathu Y, Jackson M, Ribchester RR, von Kriegsheim A, Alkuraya FS, Woods CG, Maher ER, Mill P. PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins. Am J Hum Genet. 2017 May 4;100(5):706-724.

PubMed ID: 
28413018

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy

Falik Zaccai TC, Savitzki D, Zivony-Elboum Y, Vilboux T, Fitts EC, Shoval Y, Kalfon L, Samra N, Keren Z, Gross B, Chasnyk N, Straussberg R, Mullikin JC, Teer JK, Geiger D, Kornitzer D, Bitterman-Deutsch O, Samson AO, Wakamiya M, Peterson JW, Kirtley ML, Pinchuk IV, Baze WB, Gahl WA, Kleta R, Anikster Y, Chopra AK. Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy. Brain. 2017 Feb;140(Pt 2):370-386.

PubMed ID: 
28007986

Encephalopathy, Early-Onset, With Brain Atrophy and Thin Corpus Callosum

Clinical Characteristics
Ocular Features: 

Optic atrophy is present in many patients and may be present early since lack of visual tracking or eye contact may be noted at birth.  Sparse eyebrows, upslanting palpebral fissures, and hypertelorism have also been reported.

Systemic Features: 

Severe hypotonia is present at birth often causing respiratory distress in the neonate.  Spasticity can develop later.  Growth failure with progressive microcephaly is present in infants.  Brain imaging often reveals diffuse atrophy of structures including the cerebellum, brainstem, spinal cord, and cerebrum.  Tongue fasciculations have been observed.   Micrognathia and widely spaced teeth are sometimes present.  Several patients have died during infancy.

Genetics

Homozygous mutations in the TBCD (17q25.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy

Flex E, Niceta M, Cecchetti S, Thiffault I, Au MG, Capuano A, Piermarini E, Ivanova AA, Francis JW, Chillemi G, Chandramouli B, Carpentieri G, Haaxma CA, Ciolfi A, Pizzi S, Douglas GV, Levine K, Sferra A, Dentici ML, Pfundt RR, Le Pichon JB, Farrow E, Baas F, Piemonte F, Dallapiccola B, Graham JM Jr, Saunders CJ, Bertini E, Kahn RA, Koolen DA, Tartaglia M. Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):962-973.

PubMed ID: 
27666370

Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy

Miyake N, Fukai R, Ohba C, Chihara T, Miura M, Shimizu H, Kakita A, Imagawa E, Shiina M, Ogata K, Okuno-Yuguchi J, Fueki N, Ogiso Y, Suzumura H, Watabe Y, Imataka G, Leong HY, Fattal-Valevski A, Kramer U, Miyatake S, Kato M, Okamoto N, Sato Y, Mitsuhashi S, Nishino I, Kaneko N, Nishiyama A, Tamura T, Mizuguchi T, Nakashima M, Tanaka F, Saitsu H, Matsumoto N. Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):950-961.

PubMed ID: 
27666374

PEHO Syndrome

Clinical Characteristics
Ocular Features: 

Optic atrophy is a common feature.  There may be lack of visual fixation from birth or sometimes several months later, attributed to cortical inattention.  Flash visual evoked potentials may be unrecordable. Pupillary responses to light are 'weak' and sluggish. Epicanthal folds may be seen.

Systemic Features: 

Infants are usually born with a normal head circumference but fall behind (2 SD or more) in the first year.  They have neonatal and infantile central hypotonia with brisk peripheral tendon reflexes during early childhood.  They are sometimes described as drowsy or lethargic.  Facial and limb edema can be extensive but transient sometimes and can disappear later in childhood.  The fingers are tapered.  The cheeks are full, the mouth is usually open and the upper lip appears 'tented'.  Global developmental delay is common and normal milestones are seldom attained.  Some patients have been described as severely retarded mentally.  Infantile spasms and myoclonic jerkingcan be seen within the first months of life while frank seizures with hypsarrhythmia are common in the first year of life.  Status epilepticus is a common occurrence.  General drowsiness and poor feeding are often features.  Death usually occurs in infancy or early childhood.  Midface hypoplasia and micrognathia are often present.

Brain imaging (MRI) and histology show severe alterations in myelination and cellular organization.  Neuronal loss is seen in the inner granular layer of the cerebellum but there is relative preservation of Purkinje cells.  General and progressive atrophy of the cerebellum and brain stem have been described.

Genetics

Homozygous frameshift mutations in ZNHIT3 (17q12) have been identified in affected members of several consanguineous families.  The presumed mutation seems to be most prevalent in Finland.

A somewhat similar disorder known as PEHO-like syndrome (617507) is the result of homozygous mutations in the CCDC88A gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Physical therapy to prevent contractures and general supportive care can be helpful.  Supplemental feeding may be required. 

References
Article Title: 

The PEHO syndrome

Riikonen R. The PEHO syndrome. Brain Dev. 2001 Nov;23(7):765-9. Review.

PubMed ID: 
11701291
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