cognitive defects

Optic Atrophy 10

Clinical Characteristics
Ocular Features: 

Low vision is noted in early childhood without systemic symptoms.  The optic nerves appear pale (age of onset uncertain).  The retinal nerve fiber layer may be reduced in thickness in all quadrants but only segmentally in some individuals.  No VEP can be recorded.  On brain MRI examination the optic tracts are thin.  The appearance of the optic nerve is consistent with mild hypoplasia in some patients.

Systemic Features: 

Some patients have ataxia, cognitive deficits, and seizures.  A brother and sister from a consanguineous Moroccan family and two unrelated individuals have been reported.  

Genetics

This autosomal recessive condition is caused by homozygous or compound heterozygous mutations in the RTN4IP1 gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies

Angebault C, Guichet PO, Talmat-Amar Y, Charif M, Gerber S, Fares-Taie L, Gueguen N, Halloy F, Moore D, Amati-Bonneau P, Manes G, Hebrard M, Bocquet B, Quiles M, Piro-Megy C, Teigell M, Delettre C, Rossel M, Meunier I, Preising M, Lorenz B, Carelli V, Chinnery PF, Yu-Wai-Man P, Kaplan J, Roubertie A, Barakat A, Bonneau D, Reynier P, Rozet JM, Bomont P, Hamel CP, Lenaers G. Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies. Am J Hum Genet. 2015 Nov 5;97(5):754-60. 

PubMed ID: 
26593267

Rubinstein-Taybi Syndrome 1

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity in this disorder.  Few patients have all of the clinical features and there is much variation in the severity of these.  Almost all segments of the eye can be involved.  The lashes are often lush and the eyebrows may be highly arched and bushy.  Lid fissures are often downward slanting (88%).  Congenital glaucoma, nystagmus, cataracts, lacrimal duct obstruction (37%), ptosis (29%), colobomas and numerous corneal abnormalities including keratoglobus, sclerocornea, and megalocornea have been reported.  Abnormal VEP waveforms and cone and cone-rod dysfunction have been found in the majority (78%) of patients tested.  Retinal pigmentary changes have been seen in some patients.  Refractive errors (usually myopia) occur in 56% of patients.  Visual acuities vary widely but about 20% of patients are visually handicapped.

Fluorescein angiography in a single patient revealed generalized vascular attenuation and extensive peripheral avascularity.  The AV transit time was prolonged with delayed venous filling and late small vessel leakage. 

Systemic Features: 

The facial features are reported to be characteristic but there are few distinctive signs.  The face is often broad and round, the nose is beaked, the mouth is small, and the lower lip appears to pout and protrudes beyond a short upper lip.  Smiles have been described as 'grimacing'.  It is common for the columella to protrude beyond the alae nasi.  The palate is narrow and highly arched and the laryngeal walls collapse easily which may lead to feeding problems and respiratory difficulties.  The ears may be rotated posteriorly.  The anterior hairline can appear low.

Among the more distinctive signs are the broad thumbs and great toes which are often deviated medially.  However, the distal phalanges of all fingers may be broad as well.  Bone fractures are common and patellar dislocations can be present as seen in the first two decades of life.  Hypotonia is a feature.  Numerous dental anomalies have been reported including crowded teeth, enamel hypoplasia, crossbite, and abnormal numbers of teeth.

Developmental delays are common.  Infancy and childhood milestones are often delayed.  Many patients have cognitive delays and some are mildly retarded.  Postnatal growth is subnormal and obesity is common.  A third of patients have a cardiac abnormality including septal defects, valvular defects, coarctation of the aorta, pulmonic stenosis, and patent ductus arteriosus.  Renal abnormalities occur frequently and almost all males have undescended testes.  Patients are at increased risk of tumors, both malignant and benign, many of which occur in the central nervous system.  Other problems are constipation and hearing loss.

Genetics

Evidence points to an autosomal dominant mode of inheritance secondary to mutations in CREBBP (16p13.3) but there is some genetic heterogeneity as mutations in EP300 (22q13) have been associated with a similar disease (see Rubinstein-Taybi Syndrome 2; 613684).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at specific clinical features such as glaucoma and strabismus.  Special education and vocational training may be helpful.  Hearing loss may respond to standard treatment.  Fractures and dislocations should receive prompt attention.  Cardiac anomalies may require surgical correction.

References
Article Title: 

Neurofibromatosis Type I

Clinical Characteristics
Ocular Features: 

Melanocytic iris hamartomas, sometimes called Lisch nodules, are considered pathognomonic of this disease but are found in only about 75% of patients.  These appear as sharply defined, smooth masses on the stromal surface and consist of spindle cells of melanocytic origin.  Their presence correlates with the severity of skin freckles and cafe-au-lait spots.  Also characteristic of neurofibromatosis 1 are eyelid fibromas causing ptosis and the familiar horizontal S-sign in the upper lid margin but these are only found in one-third of patients.  Ciliary body cysts have been reported to occur at a frequency of 78%, or 10 times more frequently than in unaffected individuals.  Nearly half of patients have occludable anterior chamber angles (Types 1 and 2).

Gliomas of the optic nerves, chiasm or optic tracts are slow growing astrocytomas that occur in about 15% of children at a mean age of about 5 years.  While these comprise the most common intracranial tumors in NF1, they typically have a benign course and may even regress.  However, some present as precocious puberty and severe loss of acuity may occur before discovery.

Vascular lesions of the retina are also sometimes seen and may be responsible for rubeosis and neovascular glaucoma.

Systemic Features: 

Vascular anomalies are often seen and those that impact blood supply to the kidneys can induce severe hypertension especially in children (pheochromocytomas are also a risk).  Coarctations and aneurysmal anomalies can obstruct the blood supply to major organs, sometimes acutely.  Some degree of cognitive impairment and sometimes mental retardation can be seen in nearly half of patients, even in the absence of other obvious neurological deficits.  Short stature, tibial pseudoarthrosis, sphenoid dysplasia, and scoliosis are common.  Osteopenia and frank osteoporosis are seen in approximately half of patients.  A small percentage of patients develop malignant peripheral nerve sheath tumors (lifetime risk 8-13%).  Rare patients develop other malignancies, primarily sarcomas.

Diagnosis is based on the presence of some combination of typical features such as cafe-au-lait spots, Lisch nodules, neurofibromas, optic pathway gliomas, axillary or groin freckling, and bone dysplasia.  The underlying disease is progressive and the accuracy of diagnosis improves in older patients.

Genetics

The typical disease is caused by mutations in the NF1 gene (17q11.2) and inherited as an autosomal dominant disorder.  However, about half of patients have new mutations with males having the higher mutation rate.  Penetrance is nearly 100% among those who have mutations in NF1. There is evidence that the gene product is a tumor suppressor protein (neurofibromin) and the clinical features can also result from deactivation of both copies of the gene via the two hit mechanism of Knudson.  This has been proposed as a mechanism to explain the high degree of variability of clinical disease within families as the expression depends upon which cell lines experience postzygotic somatic mutations.

Watson syndrome (193520) is also the result of NF1 mutations and shares some clinical features such as neurofibromas, Lisch nodules, shortness of stature, cognitive deficits, and cafe-au-lait spots.  It may be an allelic disorder.

Neurofibromatosis type II (101000), with less cognitive problems, results from mutations in NF2.  Lisch nodules are less common in type II but acoustic neuromas are more common than in type I.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the underlying disease but lifelong monitoring is necessary because of the widespread manifestations and serious threat of complications such as visual impairment, renal hypertension and ischemia of major organs.

References
Article Title: 

Tuberous Sclerosis 1

Clinical Characteristics
Ocular Features: 

The primary clinical characteristic of tuberous sclerosis of both types 1 and 2 are the occurrence of hamartomas at multiple anatomic sites.  Ocular lesions include those of the eyelids which often appear in early childhood along with other facial angiofibromas (formerly called adenoma sebaceum).  Of greater clinical significance are lesions of the optic nerve and retina reported in about 75% of patients.  The latter (astrocytic hamartomas) may appear as mulberry-like growths typically located in the peripapillary area or as flat translucent lesions located more peripherally.  These are usually static but aggressive growth with retinal detachment and neovascular glaucoma requiring enucleation has been reported in several patients.  Calcification of these lesions may occur in utero or early in life.  These are seldom of clinical significance although optic atrophy has been reported. The iris may have hypopigmented areas.

Systemic Features: 

Hamartomas develop throughout the body in many organs such as the skin, brain, eye, kidney, and heart.  Ninety per cent of patients have skin lesions, including hypomelanotic patches called 'ashleaf' spots that can best be visualized under a Woods lamp.  Symptoms vary widely depending upon the location and size of the growths.  These appear as rhabdomyomas in the heart, angiomyolipomas in the kidneys, bone cysts, and oral fibromas.  Other intracranial growths such as subependymal astrocytomas and cortical tubers are evidence of CNS involvement that can interfere with brain function leading to seizures (in 80% of patients) and subnormal intellectual abilities (60-70% patients) as manifested by learning difficulties, subnormal IQs, as well as social and communication difficulties.   Hypoplasia of dental enamel with pitting in permanent teeth is seen in the majority of patients.  Some progression of tumor size and symptoms may occur.  Most hamartomas are benign but renal carcinoma has been reported in some patients.

Genetics

Many cases (two-thirds) occur sporadically but numerous reported pedigrees are consistent with autosomal dominant inheritance.  Type 1 TSC is caused by mutations in the TSC1 gene (9p34) encoding hamartin and is responsible for the disorder in about 25% of patients.

A more severe phenotype, tuberous sclerosis 2 (613254), is caused by mutations in the TSC2 gene on chromosome 16p13.3 and accounts for the majority of cases of tuberous sclerosis complex.  Genotyping is necessary to determine which mutation is responsible for the TS complex in each case as the phenotypic differences are inadequate to distinguish clinically between types 1 and 2.

New mutations are responsible for 50-70% of cases.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective preventative treatment exists but individual lesions can be surgically removed when indicated.

References
Article Title: 

Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34

van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, Lindhout D, van den Ouweland A, Halley D, Young J, Burley M, Jeremiah S, Woodward K, Nahmias J, Fox M, Ekong R, Osborne J, Wolfe J, Povey S, Snell RG, Cheadle JP, Jones AC, Tachataki M, Ravine D, Sampson JR, Reeve MP, Richardson P, Wilmer F, Munro C, Hawkins TL, Sepp T, Ali JB, Ward S, Green AJ, Yates JR, Kwiatkowska J, Henske EP, Short MP, Haines JH, Jozwiak S, Kwiatkowski DJ. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997 Aug 8;277(5327):805-8.

PubMed ID: 
9242607

Tuberous sclerosis

Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008 Aug 23;372(9639):657-68. Review.

PubMed ID: 
18722871

Cataracts, Congenital, Facial Dysmorphism, and Neuropathy

Clinical Characteristics
Ocular Features: 

Cataracts, microphthalmia, and microcornea (mean diameter ~7.5 mm) are present at birth and precede the onset of neurological symptoms.  The lens opacities often consist of anterior and posterior subcapsular opacities but the entire lens may be opaque as well.  Some adults have bilateral ptosis.  The pupils are often small and have sluggish responses to light and mydriatics.  Strabismus and horizontal pendular nystagmus are common.  Visual impairment may be severe.

Systemic Features: 

The neuropathy is primarily motor and usually begins in the lower extremities but is progressive and eventually involves the arms as well.  Motor development is slow and walking is often unsteady from the start.  Speaking may not have its onset until 3 years of age.   Mild, nonprogresssive cognitive defects and mental retardation are often present.  Sensory neuropathy with numbness and tingling develops in the second decade.  Mild chorea, upper limb tremor, mild ataxia, and extensor plantar responses may be seen.  Deafness has been described.  Nerve conduction studies and biopsies have documented a demyelinating polyneuropathy while MRIs demonstrate cerebral and spinal cord atrophy which may be seen in the first decade of life.  The MRI in many patients reveals diffuse cerebral atrophy, enlargement of the lateral ventricles and focal lesions in subcortical white matter.  Most individuals have mild cognitive deficits while psychometric testing reveals borderline intelligence in a minority.

Patients are susceptible to acute rhabdomyolysis following viral infections.  Most are severely disabled by the third decade.

The facial dysmorphism appears in childhood and consists of a prominent midface, hypognathism, protruding teeth, and thickening of the lips.  Spinal deformities occur in the majority of individuals along with foot and hand claw deformities.  All patients are short in stature.  Hypogonadotropic hypogonadism is a common feature and females may be infertile.  Amenorrhea is often present by the age of 25-35 years.

Genetics

This is an autosomal recessive disorder found primarily among European Gypsies.  It is caused by mutations in the CTDP1 gene (18q23-qter).  It is sometimes confused with Marinesco-Sjogren syndrome (248800) with which it shares some clinical features but the two are genetically distinct.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts often require removal in the first decade of life. Scoliosis and foot deformities may benefit from surgical correction.  Supportive care and physical therapy can be helpful.

References
Article Title: 

Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome

Lagier-Tourenne C, Chaigne D, Gong J, Flori J, Mohr M, Ruh D, Christmann D, Flament J, Mandel JL, Koenig M, Dollfus H. Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome. J Med Genet. 2002 Nov;39(11):838-43.

PubMed ID: 
12414825

Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations

Tournev I, Kalaydjieva L, Youl B, Ishpekova B, Guergueltcheva V, Kamenov O, Katzarova M, Kamenov Z, Raicheva-Terzieva M, King RH, Romanski K, Petkov R, Schmarov A, Dimitrova G, Popova N, Uzunova M, Milanov S, Petrova J, Petkov Y, Kolarov G, Aneva L, Radeva O, Thomas PK. Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations. Ann Neurol. 1999 Jun;45(6):742-50.

PubMed ID: 
10360766
Subscribe to RSS - cognitive defects