failure to thrive

Hypotonia, Infantile, with Psychomotor Retardation And Characteristic Facies 2

Clinical Characteristics
Ocular Features: 

Anomalies of periocular structures are part of the characteristic facial morphology.  The lid fissures slant downward and epicanthal folds are with ptosis are generally present.  Strabismus and nystagmus are characteristic features.

Systemic Features: 

This is a severe congenital neurodevelopmental disorder with global delay, hypotonia, and characteristic facies.  It is usually present at birth and soon manifest as a profound intellectual delay.  Most patients do not develop speech or independent motor skills.  Feeding difficulties are evident early and often require gastric tube placement for nutrition.  Failure to thrive is common.   Most patients have seizures of a tonic-clonic or atonic type which may be controlled with medication. 

Microcephaly, brachycephaly, plagiocephaly, and brachycephaly have been described.  A high forehead with frontal bossing, facial hypotonia, triangular facies have been described.  The ears are low-set and posteriorly rotated.  The upper lip is often thin and the mouth is commonly open.  The neck appears short, the nose is bulbous while the nasal bridge is prominent and the nares may be anteverted.

Brain imaging is normal in some patients but there is evidence of generalized cerebral atrophy, with a thin corpus callosum and decreased myelination in others.  Variable features such as scoliosis, hip contractures, muscle wasting, and dyskinesias are sometimes seen.

Genetics

This disorder is caused by homozygous or compound heterozygous mutations in the UNC80 gene (2q34).  

For somewhat similar disorders see IHPRF1 (615419) and IHPRF3 (616900).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability

Stray-Pedersen A, Cobben JM, Prescott TE, Lee S, Cang C, Aranda K, Ahmed S, Alders M, Gerstner T, Aslaksen K, Tetreault M, Qin W, Hartley T, Jhangiani SN, Muzny DM, Tarailo-Graovac M, van Karnebeek CD; Care4Rare Canada Consortium; Baylor-Hopkins Center for Mendelian Genomics, Lupski JR, Ren D, Yoon G. Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability. Am J Hum Genet. 2016 Jan 7;98(1):202-9.

PubMed ID: 
26708751

UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN

Perez Y, Kadir R, Volodarsky M, Noyman I, Flusser H, Shorer Z, Gradstein L, Birnbaum RY, Birk OS. UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN. J Med Genet. 2016 Jun;53(6):397-402.

PubMed ID: 
26545877

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

ZTTK Syndrome

Clinical Characteristics
Ocular Features: 

The eyes are deep-set and the palpebral fissures slant downward.  Optic atrophy is often present.  The majority of individuals have poor visual responses which may also be attributed to central or cortical impairment.  Strabismus and nystagmus are frequently present.

Systemic Features: 

ZTTK syndrome is multisystem malformation and developmental disorder with a heterogeneous clinical presentation.  The facial features might suggest the diagnosis at birth but most of the signs are nonspecific including frontal bossing, underdevelopment of the midface, facial asymmetry, low-set ears, broad and/or depressed nasal bridge, and a short philtrum.  Poor feeding and hypotonia in the neonatal period are usually present and physical growth is subnormal resulting in short stature.

Brain imaging may show abnormal gyral patterns, ventriculomegaly, hypoplasia of the corpus callosum, cerebellar hypoplasia, arachnoid cysts, and loss of periventricular white matter.  About half of patients develop seizures and many have intellectual disabilities.  Spinal anomalies include hemivertebrae with scoliosis and/or kyphosis.  Other skeletal features include joint laxity in some patients and contractures in others.  Arachnodactyly, craniosynostosis, and rib anomalies have been reported.  There may be malformations in the GI, GU, and cardiac systems while immune and coagulation abnormalities have also been reported.

Genetics

Heterozygous mutations in the SON gene (21q22.11) have been identified in patients with this condition.  They may cause truncation of the gene product with haploinsufficiency or, in other patients, a frameshift in the reading.  The SON gene is a master RNA splicing regulator that impacts neurodevelopment.

Virtually all cases are the result of de novo mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment has been reported.  Physical therapy and assistive devices may be helpful.

References
Article Title: 

De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive

Tokita MJ, Braxton AA, Shao Y, Lewis AM, Vincent M, Kury S, Besnard T, Isidor B, Latypova X, Bezieau S, Liu P, Motter CS, Melver CW, Robin NH, Infante EM, McGuire M, El-Gharbawy A, Littlejohn RO, McLean SD, Bi W, Bacino CA, Lalani SR, Scott DA, Eng CM, Yang Y, Schaaf CP, Walkiewicz MA. De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive. Am J Hum Genet. 2016 Sep 1;99(3):720-7.

PubMed ID: 
27545676

De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Kim JH, Shinde DN, Reijnders MR, Hauser NS, Belmonte RL, Wilson GR, Bosch DG, Bubulya PA, Shashi V, Petrovski S, Stone JK, Park EY, Veltman JA, Sinnema M, Stumpel CT, Draaisma JM, Nicolai J; University of Washington Center for Mendelian Genomics, Yntema HG, Lindstrom K, de Vries BB, Jewett T, Santoro SL, Vogt J; Deciphering Developmental Disorders Study, Bachman KK, Seeley AH, Krokosky A, Turner C, Rohena L, Hempel M, Kortum F, Lessel D, Neu A, Strom TM, Wieczorek D, Bramswig N, Laccone FA, Behunova J, Rehder H, Gordon CT, Rio M, Romana S, Tang S, El-Khechen D, Cho MT, McWalter K, Douglas G, Baskin B, Begtrup A, Funari T, Schoch K, Stegmann AP, Stevens SJ, Zhang DE, Traver D, Yao X, MacArthur DG, Brunner HG, Mancini GM, Myers RM, Owen LB, Lim ST, Stachura DL, Vissers LE, Ahn EY. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome. Am J Hum Genet. 2016 Sep 1;99(3):711-9.

PubMed ID: 
27545680

Mitochondrial DNA Depletion Syndrome 3

Clinical Characteristics
Ocular Features: 

Nystagmus, disconjugate eye movements, and "optic dysplasia" have been noted.

Systemic Features: 

Infants feed poorly which is frequently associated with vomiting, failure to thrive, and growth delay.  They are hypothermic, hypoglycemic, and often jaundiced with signs of liver failure noted between birth and 6 months of age and death by approximately 1 year of age.  Hepatosplenomegaly is present early with abnormal liver enzymes, cholestasis, steatosis, and hepatocellular loss followed by cirrhosis with portal hypertension.  Metabolic acidosis, hyperbilirubinemia, hypoalbuminemia, and hypoglycemia are often present.  Mitochondrial DNA depletion in the liver approaches 84-90%.

All patients have encephalopathic signs with evidence of cerebral atrophy, microcephaly, hypotonia.  Hyperreflexia may be present and some infants have seizures.  Muscle tissue, however, has normal histology and respiratory chain activity.

Genetics

This disorder results from homozygous or compound heterozygous mutations in the DGUOK gene (2p13).

The same gene is mutated in PEOB4 (617070).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no effective treatment.  Liver transplantation in one infant was unsuccessful.  

References
Article Title: 

Vici Syndrome

Clinical Characteristics
Ocular Features: 

Congenital cataracts, both unilateral and bilateral are common.  The fundus appears hypopigmented. Nystagmus, optic neuropathy, and mild ptosis have been reported.  Nothing is known regarding acuity. 

Systemic Features: 

Infants at birth have striking hypotonia with a weak cry and feeding difficulties.  Dysmorphic features such as micrognathia, microcephaly, low-set ears, some degree of generalized hypopigmentation (hair and skin), and a broad nose with a long philtrum may be present. The face may appear triangular.  Cleft lip and palate may be present.  Evidence of cardiac dysfunction may also be present early with both dilated and hypertrophic cardiomyopathy reported.  Hearing loss has been reported in some individuals.  Recurrent infections are common and immunologic studies have revealed, in some patients, granulocytopenia, low T cell counts (primarily T4+ cells), thymic dysplasia, and low levels of IgG.  Seizures may occur.  Liver dysfunction has been variably reported.

Neurological and brain evaluations have reported agenesis of the corpus callosum, defects in the septum pellucidum, and hypoplasia of the cerebellar vermis along with pontocerebellar hypoplasia.  Psychomotor retardation is severe in most individuals along with general growth retardation.

Histologic studies of skeletal muscle fibers have shown considerable variation in fiber size, centralized nuclei, fucsinophilic inclusions, and enlarged abnormal mitochondria.  Other central nervous system abnormalities include in some individuals a paucity of white matter, schizencephaly, neuronal heterotopias, and enlargement of the ventricles.

The cumulative effects of these multiorgan abnormalities lead to death within the first year or two of life, generally of heart failure or sepsis. 

Genetics

Homozygous or compound heterozygous mutations in the EPG5 gene (18q12.3) have been associated with this condition.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Vici syndrome: a

Byrne S, Dionisi-Vici C, Smith L, Gautel M, Jungbluth H. Vici syndrome: a
review. Orphanet J Rare Dis. 2016 Feb 29;11(1):

PubMed ID: 
4772338

Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy

Cullup T, Kho AL, Dionisi-Vici C, Brandmeier B, Smith F, Urry Z, Simpson MA, Yau S, Bertini E, McClelland V, Al-Owain M, Koelker S, Koerner C, Hoffmann GF, Wijburg FA, ten Hoedt AE, Rogers RC, Manchester D, Miyata R, Hayashi M, Said E, Soler D, Kroisel PM, Windpassinger C, Filloux FM, Al-Kaabi S, Hertecant J, Del Campo M, Buk S, Bodi I, Goebel HH, Sewry CA, Abbs S, Mohammed S, Josifova D, Gautel M, Jungbluth H. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat Genet. 2013 Jan;45(1):83-7.

PubMed ID: 
23222957

Infantile Cerebellar-Retinal Degeneration

Clinical Characteristics
Ocular Features: 

Visual tracking can be normal during the newborn period but lack of visual fixation and attention soon become evident.  Strabismus, nystagmus, and abnormal pursuit movements are often present.  Optic atrophy has been reported as early as 3 years of age.  VEP and ERG responses are extinguished in the first two years. The nystagmus may be multidirectional.  Acuity loss seems to be progressive.  A progressive retinal degeneration (not further characterized) has been reported.

Systemic Features: 

Infants generally appear normal at birth.  Within the first 6 months they show signs of developmental delay and neurological signs such as truncal hypotonia, seizures, athetosis and head bobbing.  Milestones of sitting, rolling over, and reactions to others are seldom achieved.  Cerebellar brain imaging shows progressive atrophy in all patients and some have cortical atrophy as well.  Some patients have evidence of hearing loss.   Severe failure to thrive and psychomotor delays are usually present.  Death may occur within several months of birth although some live for several decades.

Genetics

This condition results from homozygous or compound heterozygous mutations in the ACO2 gene (22q13.2).  The mutation has also been associated with optic atrophy 9 (616289).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond supportive care is known.

References
Article Title: 

Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy

Metodiev MD, Gerber S, Hubert L, Delahodde A, Chretien D, Gerard X, Amati-Bonneau P, Giacomotto MC, Boddaert N, Kaminska A, Desguerre I, Amiel J, Rio M, Kaplan J, Munnich A, Rotig A, Rozet JM, Besmond C. Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. J Med Genet. 2014 Dec;51(12):834-8.

PubMed ID: 
25351951

Gracile Bone Dysplasia

Clinical Characteristics
Ocular Features: 

The eyes have been described as small.  Aniridia may be present.

Systemic Features: 

This is a usually fatal form of skeletal dysplasia with splenic and ocular features as well.  In utero death is not uncommon while newborns may not survive the neonatal period.  The face has been described as dysmorphic with a high forehead, flat nasal bridge, a cloverleaf-shaped skull, and hypoplastic cranial bones with premature suture closure.  The long bones are dysplastic as well with thinned diaphyses (sometimes fractured in utero), growth plate disorganization, excessive remodeling, and signs of arrested growth.  The ribs share in the dysplasia but pulmonary hypoplasia has also been described.  Most individuals have short limbs.

The spleen can be hypoplastic or aplastic and ascites has been noted in several infants.  Failure to thrive is common and seizures have been reported.  Males may have micropenis and hypospadias while females have been described with labial fusion.  

Low parathyroid hormone levels and hypocalcemia has been reported in most individuals.

Genetics

Heterozygous mutations in the FAM111A gene (11q12.1) have been associated with this disorder.  The functional role of FAM111A products is unknown but likely play a role in calcium metabolism, parathyroid hormone secretion, and osseous development.

Mutations in the same gene can be responsible for the allelic autosomal dominant Kenny-Caffey syndrome (127000) with some similar features.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

FAM111A mutations result in hypoparathyroidism and impaired skeletal development

Unger S, Gorna MW, Le Bechec A, Do Vale-Pereira S, Bedeschi MF, Geiberger S, Grigelioniene G, Horemuzova E, Lalatta F, Lausch E, Magnani C, Nampoothiri S, Nishimura G, Petrella D, Rojas-Ringeling F, Utsunomiya A, Zabel B, Pradervand S, Harshman K, Campos-Xavier B, Bonafe L, Superti-Furga G, Stevenson B, Superti-Furga A. FAM111A mutations result in hypoparathyroidism and impaired skeletal development. Am J Hum Genet. 2013 Jun 6;92(6):990-5.

PubMed ID: 
23684011

Orofaciodigital Syndrome, Type VI

Clinical Characteristics
Ocular Features: 

Hypertelorism and epicanthal folds have been described.  Some patients have nystagmus and strabismus. Ocular apraxia and difficulties in smooth visual pursuit may be present.   

Systemic Features: 

Polydactyly of the hands is a common feature.  The central metacarpal is often Y-shaped leading to ‘central polydactyly’.  The large toes may be bifid.  Cognitive deficits are common and some patients have been considered mentally retarded.  The ears are low-set and rotated posteriorly.  Some patients have a conductive hearing loss.  Oral anomalies may include a lobed tongue, lingual and sublingual hemartomas, micrognathia, clefting, and multiple buccoalveolar frenula.  Congenital heart anomalies, micropenis, and cryptorchidism have been reported.  Tachypnea and tachycardia have been noted.  Some patients have some degree of skeletal dysplasia and many individuals are short in stature.

The presence of cerebellar abnormalities such as hypoplasia (including absence) of the vermis may help to distinguish type VI from other forms of OFDS.  Hypothalamic dysfunction may be responsible for poor temperature regulation (hyperthermia). The ‘molar tooth sign’ seen on brain MRIs in Joubert syndrome (213300) is also present in OFDS VI. 

Genetics

This is a rare condition with limited family information.  Parents in one family were consanguineous, and multiple affected sibs in other families suggest this may be an autosomal recessive condition.  Homozygous mutations in TMEM216 have been found. Other patients have mutations in C5orf42.

Many of the clinical features in OFDS VI are also found among individuals with Joubert (213300) and Meckel (249000) syndromes that also sometimes have mutations in the TMEM216 and C5orf42 genes.  Some consider all of these conditions to be members of a group of overlapping disorders called ciliopathies or ciliary dyskinesias.   

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available for this syndrome but individual signs and symptoms may need treatment.

References
Article Title: 

C5orf42 is the major gene responsible for OFD syndrome type VI

Lopez E, Thauvin-Robinet C, Reversade B, Khartoufi NE, Devisme L, Holder M, Ansart-Franquet H, Avila M, Lacombe D, Kleinfinger P, Kaori I, Takanashi JI, Le Merrer M, Martinovic J, No?'l C, Shboul M, Ho L, G?oven Y, Razavi F, Burglen L, Gigot N, Darmency-Stamboul V, Thevenon J, Aral B, Kayserili H, Huet F, Lyonnet S, Le Caignec C, Franco B, Rivi?(r)re JB, Faivre L, Atti?(c)-Bitach T. C5orf42 is the major gene responsible for OFD syndrome type VI. Hum Genet. 2013 Nov 1. [Epub ahead of print].

PubMed ID: 
24178751

Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes

Valente EM, Logan CV, Mougou-Zerelli S, Lee JH, Silhavy JL, Brancati F, Iannicelli M, Travaglini L, Romani S, Illi B, Adams M, Szymanska K, Mazzotta A, Lee JE, Tolentino JC, Swistun D, Salpietro CD, Fede C, Gabriel S, Russ C, Cibulskis K, Sougnez C, Hildebrandt F, Otto EA, Held S, Diplas BH, Davis EE, Mikula M, Strom CM, Ben-Zeev B, Lev D, Sagie TL, Michelson M, Yaron Y, Krause A, Boltshauser E, Elkhartoufi N, Roume J, Shalev S, Munnich A, Saunier S, Inglehearn C, Saad A, Alkindy A, Thomas S, Vekemans M, Dallapiccola B, Katsanis N, Johnson CA, Atti?(c)-Bitach T, Gleeson JG. Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet. 2010 Jul;42(7):619-25.

PubMed ID: 
20512146

Peroxisome Biogenesis Disorder 3B (Infantile Refsum Disease)

Clinical Characteristics
Ocular Features: 

This peroxisomal disorder presents in the first year of life with both systemic and ocular features.  Night blindness is the major ocular feature and at least some have optic atrophy similar to the adult form.  Nystagmus may be present.  Reduction or absence of rod responses on ERG can be used in young children to document the retinopathy. Blindness and deafness commonly occur in childhood.

Systemic Features: 

This disorder is classified as a peroxisomal biogenesis disorder (PBD) associated with the breakdown of phytanic acid.  Ataxia and features of motor neuron disease are evident early.  Hepatomegaly and jaundice may also be an early diagnostic feature as bile acid metabolism is defective.  Infant hypotonia is often seen.  Nonspecific facial dysmorphism has been reported as a feature. The teeth are abnormally large and often have yellowish discoloration.  Postural unsteadiness is evident when patients begin walking.  Diagnosis can be suspected from elevated serum phytanic and pipecolic acid (in 20% of patients) or by demonstration of decreased phytanic acid oxidation in cultured fibroblasts.  Other biochemical abnormalities such as hypocholesterolemia and elevated very long chain fatty acids and trihydroxycholestanoic acid are usually present.  Anosmia and mental retardation are nearly universal features.  Early mortality in infancy or childhood is common although some survive into the 2nd and 3rd decades.

Genetics

This is an autosomal recessive peroxisomal biogenesis disorder (PBD) resulting from mutations in a number of PEX genes (PEX1, PEX2, PEX3, PEX12, PEX26).  It shares many features with other PBDs including those formerly called Zellweger syndrome (214100), rhizomelic chondrodysplasia punctata (215100), and neonatal adrenoleukodystrophy (601539).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Congenital Disorder of Glycosylation, Type Ia

Clinical Characteristics
Ocular Features: 

Strabismus, roving eye movements (and nystagmus), and visual inattention are found in nearly all patients. Esotropia with defective abduction seems to be the most common oculomotor finding and may be present at birth.  Cataracts, ocular colobomas, oculomotor apraxia, disc pallor, and glaucoma have also been reported.  Vision is always subnormal. Reports of ocular disease before modern genotyping are not specific to the subtypes of CDG I now recognized.

This is a congenital, progressive disorder of photoreceptor degeneration with a later onset of progressive pigmentary retinopathy.  It is described in some cases as a typical retinitis pigmentosa.  The ERG is abnormal in all patients even if the pigmentary pattern is atypical for RP.  Rod responses are usually absent while the cone b-wave implicit time is delayed.  The degree of photoreceptor damage is variable, however.  Extended retinal function among younger patients suggest that the ‘on-pathway’ evolving synapses in the outer plexiform layer among photoreceptors, bipolar cells, and horizontal cells is severely dysfunctional.

Systemic Features: 

This is a multisystem disorder, often diagnosed in the neonatal period by the presence of severe encephalopathy with hypotonia, hyporeflexia, and poor feeding.  Failure to thrive, marked psychomotor retardation, delayed development, growth retardation, and ataxia become evident later in those who survive.  Cerebellar and brainstem atrophy with a peripheral neuropathy can be demonstrated during late childhood.  Some older patients have a milder disease, often with muscle atrophy and skeletal deformities such as kyphoscoliosis and a fusiform appearance of the digits.  Maldistribution of subcutaneous tissue is often seen resulting in some dysmorphism, especially of the face.  Hypogonadism and enlargement of the labia majora are commonly present.  Some patients have evidence of hepatic and cardiac dysfunction which together with severe infections are responsible for a 20% mortality rate in the first year of life.

Genetics

This is one of a group of genetically (and clinically) heterogeneous autosomal recessive conditions caused by gene mutations that result in enzymatic defects in the synthesis and processing of oligosaccharides onto glycoproteins. This type (Ia) is the most common.   The mutation lies in the PMM2 gene (16p13.2).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Most children require tube feeding with nutritional supplements.  The risk of systemic infections is high.  Those patients who survive into the second decade and beyond may require orthopedic procedures and are confined to wheelchairs.  Physical, occupational, and speech therapy along with parental support are important.

References
Article Title: 

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