psychomotor delays

Joubert Syndrome and Related Disorders

Clinical Characteristics

Ocular Features

Ocular findings like systemic features are highly variable both within and between families.  Vision can be normal but in other patients it is severely reduced to the range of 20/200.  The pupils may respond sluggishly or even paradoxically to light.  ERG recordings have been reported to be normal in some patients, but absent or reduced in others.  The fundus appearance is often normal but in other individuals the pigmentation is mottled, the retinal arterioles are attenuated, and the macula has a cellophane maculopathy.  Drusen and colobomas are sometimes seen in the optic nerve while occasional patients have typical chorioretinal colobomas.  The eyebrows are often highly arched.

The oculomotor system is frequently involved.  Apraxia to some degree is common with most patients having difficulty with smooth pursuit and saccadic movements.  Compensatory head thrusting is often observed.  A pendular nystagmus may be present while esophoria or esotropia is present in many patients.

Systemic Features

There is a great deal of clinical heterogeneity in this group of ciliary dyskinesias.  Developmental delays, cognitive impairment, truncal ataxia, breathing irregularities, and behavioral disorders are among the more common features.  Hyperactivity and aggressiveness combined with dependency require constant vigilance and care.  Postaxial polydactyly is a feature of some cases.  Hypotonia is evident at birth.  Liver failure and renal disease develop in many individuals.  Neuroimaging of the midbrain-hindbrain area reveals agenesis or some degree of dysgenesis of the vermis with the ‘molar tooth sign’ in the isthmus region considered to be a diagnostic sign.  The fourth ventricle is usually enlarged while the cerebellar hemispheres may be hypoplastic.

The facies features are said to be distinctive in older individuals.  The face appears long with frontal prominence due to bitemporal narrowing, the nasal bridge and tip are prominent, the jaw is prominent, the lower lip protrudes, and the corners of the mouth are turned down.

Genetics

This is a clinically and genetically heterogeneous group of disorders with many overlapping features.  Most disorders in this disease category, known as JSRD, are inherited in an autosomal recessive pattern.  Mutations in at least 18 genes have been identified.  One, OFD1 (300804), is located on the X chromosome (Xp22.2).

There are significant clinical similarities with Meckel syndrome (249000) and with Smith-Lemli-Opitz syndrome (270400).

Treatment Options

Treatment is mostly for specific symptoms such as respiratory distress, renal disease, speech and physical therapy, low vision, and hepatic failure.

References

Poretti A, Huisman TA, Scheer I, Boltshauser E. Joubert syndrome and related disorders: spectrum of neuroimaging findings in 75 patients. AJNR Am J Neuroradiol. 2011 Sep;32(8):1459-63. Epub 2011 Jun 16.

PubMed ID: 
21680654

Sturm V, Leiba H, Menke MN, Valente EM, Poretti A, Landau K, Boltshauser E. Ophthalmological findings in Joubert syndrome. Eye (Lond). 2010 Feb;24(2):222-5.

PubMed ID: 
19461662

Braddock SR, Henley KM, Maria BL. The face of Joubert syndrome: a study of dysmorphology and anthropometry. Am J Med Genet A. 2007 Dec 15;143A(24):3235-42.

PubMed ID: 
18000967

Fennell EB, Gitten JC, Dede DE, Maria BL. Cognition, behavior, and development in Joubert syndrome. J Child Neurol. 1999 Sep;14(9):592-6.

PubMed ID: 
10488904

Spastic Ataxia 4, mtPAP Deficiency

Clinical Characteristics

Ocular Features

Ocular examinations in 4 adult individuals of a single family aged 18 to 27 years were reported to have optic atrophy.  One of these had a horizontal nystagmus and another was described as having a vertical nystagmus.  No ocular evaluations were available for 2 children, aged 2 and 6 years.  Visual acuity testing was not reported but all individuals participated appropriately in family and educational activities. 

Systemic Features

This is a congenital disorder with cerebral ataxia (limb and truncal), spastic paraparesis (increased lower limb tone with brisk knee jerks and extensor plantar responses), cerebellar and spastic dysarthria, learning difficulties and emotional lability as prominent features.  The onset of both speech and mobility are delayed.  Older individuals have slow and spastic tongue movements with brisk jaw jerks, and increased tone in the upper limbs.  Motor function progressively declines although even older individuals in the third decade of life remain mobile albeit with an increasingly spastic and ataxic gait, and require only minimal assistance with self-care.  Children in grade school require special education accommodations but there is no obvious deterioration in intellectual function as they mature.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the MTPAP gene (10p11.22).  The mutation leads to a defect of mitochondrial mRNA maturation in which the poly(A) tails are severely truncated.

Optic atrophy is also present in some patients who have autosomal dominant spastic ataxia with miosis (SPAX7) (108650) and in another form of autosomal recessive childhood-onset spastic ataxia and mental retardation (270500).

Treatment Options

No treatment is known but special education and physical and speech therapy may be helpful.

References

Crosby AH, Patel H, Chioza BA, Proukakis C, Gurtz K, Patton MA, Sharifi R, Harlalka G, Simpson MA, Dick K, Reed JA, Al-Memar A, Chrzanowska-Lightowlers ZM, Cross HE, Lightowlers RN. Defective mitochondrial mRNA maturation is associated with spastic ataxia. Am J Hum Genet. 2010 Nov 12;87(5):655-60.

PubMed ID: 
20970105

Leber Congenital Amaurosis

Clinical Characteristics

Ocular Features

Leber congenital amaurosis is a collective term applied to multiple recessively inherited conditions with early-onset retinal dystrophy causing infantile or early childhood blindness.  There are no established diagnostic criteria.  First signs are usually noted before the age of 6 months.  These consist of a severe reduction in vision accompanied by nystagmus, abnormal pupillary responses, and photophobia.  Ametropia in the form of hyperopia is common.  Keratoconus (and keratoglobus) is frequently found in older children but it is uncertain if this is a primary abnormality or secondary to eye rubbing as the latter is commonly observed.  Repeated pressure on the eye may also be responsible for the relative enophthalmos often seen in these patients.  The ERG is reduced or absent early and permanently.  Final visual acuity is seldom better than 20/400 and perhaps one-third of affected individuals have no light perception.  Some individuals experience a period of vision improvement.

The retina usually has pigmentary changes but these are not diagnostic.  Retinal vessels are generally attenuated.  The RPE may have a finely granulated appearance or, in some cases, whitish dots, and even ‘bone spicules’.

Systemic Features

A variety of metabolic and physical abnormalities have been reported with LCA but many publications are from the pre-genomic era and the significance of such associations remains uncertain.  Most extraocular signs result from delays in mental development but it is uncertain what role, if any, that visual deprivation plays.  Perhaps 20% of patients are mentally retarded or have significant cognitive deficits.

Genetics

Leber congenital amaurosis is genetically heterogeneous with 17 known gene mutations associated with the phenotype.  It is also clinically heterogeneous both within and among families and this is the major obstacle to the delineation of individual clinicogenetic entities.  As more patients are genotyped, it is likely that more precise genotype-phenotype correlations will emerge.  At the present time, however, it is not possible to use clinical findings alone to distinguish individual conditions.

Below are links to the genotypic and phenotypic features of the 17 known types of LCA.  All cause disease in the homozygous or compound heterozygous state. 

LCA type               OMIM#                 Locus              Gene Symbol   

LCA 1                    204000                 7p13.1                 GUCY2D

LCA 2                    204100                 1p31                    RPE65**

LCA 3                    604232                 14q31.3               SPATA7

LCA 4                    604393                 17p13.1               AIPL1

LCA 5                    604537                 6q14.1                 LCA5

LCA 6                    613826                 14q11                  RPGRIP1

LCA 7                    613829                19q13.1                CRX*

LCA 8                    613835                 1q31-q32             CRB1

LCA 9                    608553                 1p36                    NMNAT1

LCA 10                  611755                 12q21                  CEP290

LCA 11                  613837                 7q31.3-q332        IMPDH1

LCA 12                  610612                 1q32.3                 RD3

LCA 13                  612712                 14q24.1               RDH12

LCA 14                  613341                 4q31                    LRAT

LCA 15                  613843                 6P21-31              TULP1

LCA 16                  614186                 2q37                    KCNJ13

LCA 17                  615360                 8q22.1                 GDF6

It is likely that more mutant genes will be identified since these are found in only about half of patients studied in large series.  

*(Heterozygous mutations in CRX may also cause a cone-rod dystrophy).

**(Mutations in RPE65 has been described as also causing retinitis pigmentosa (RP20; 613794)  with choroidal involvement.)

Mutations in the GUCY2D gene seem to be the most common being present in about 21% of LCA patients with CRB1 next at 10%.

Treatment Options

Until recently, no treatment was available for LCA.  However, results from early clinical trials with adeno-associated virus vector mediated gene therapy for RPE65 mutations in LCA 2 show promise.  Subretinal placement of recombinant  adeno-virus carrying RPE65 complementary DNA results in both subjective and objective improvements in visual function.  Patients generally report subjective improvement in light sensitivity and visual mobility.  Some recovery of rod and cone photoreceptor function has been documented.  Studies have also documented an improvement in visual acuity, size of visual field, pupillary responses, and in the amouunt of nystagmus.  More than 230 patients have now  been treated and improvements seem to be maintained for at least 3 or more years.  However, we have also learned that along with the enzymatic dysfunction of RPE65 that disrupts the visual cycle, there is also degeneration of photoreceptors which continues after treatment and the long term prognosis remains guarded. Multiple phase I clinical trials have demonstrated the safety of this approach and phase III trials are now underway.

It is crucial for patients to be enrolled early in sensory stimulation programs to ensure optimum neural development.  For patients with residual vision, low vision aids can be beneficial.  Vocational and occupational therapy should be considered for appropriate patients.

References

Arcot Sadagopan K, Battista R, Keep RB, Capasso JE, Levin AV. Autosomal-dominant Leber Congenital Amaurosis Caused by a Heterozygous CRX Mutation in a Father and Son. Ophthalmic Genet. 2013 Oct 4. [Epub ahead of print] PubMed PMID: 24093488.

PubMed ID: 
24093488

Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I, Ren H, Chen Y, Li Y,
Fishman GA, Genead M, Schwartzentruber J, Solanki N, Traboulsi EI, Cheng J, Logan
CV, McKibbin M, Hayward BE, Parry DA, Johnson CA, Nageeb M; Finding of Rare
Disease Genes (FORGE) Canada Consortium, Poulter JA, Mohamed MD, Jafri H, Rashid
Y, Taylor GR, Keser V, Mardon G, Xu H, Inglehearn CF, Fu Q, Toomes C, Chen R.
Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease
pathway for retinal degeneration
. Nat Genet. 2012 Jul 29.
 

PubMed ID: 
22842230

Bowne SJ, Humphries MM, Sullivan LS, Kenna PF, Tam LC, Kiang AS, Campbell M, Weinstock GM, Koboldt DC, Ding L, Fulton RS, Sodergren EJ, Allman D, Millington-Ward S, Palfi A, McKee A, Blanton SH, Slifer S, Konidari I, Farrar GJ, Daiger SP, Humphries P. A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement. Eur J Hum Genet. 2011 Oct;19(10):1074-81. Erratum in: Eur J Hum Genet. 2011 Oct;19(10):1109.

PubMed ID: 
21654732

Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008 Oct;19(10):979-90.

PubMed ID: 
18774912

Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2231-9.

PubMed ID: 
18441371

Zernant J, Külm M, Dharmaraj S, den Hollander AI, Perrault I, Preising MN, Lorenz B, Kaplan J, Cremers FP, Maumenee I, Koenekoop RK, Allikmets R. Genotyping microarray (disease chip) for Leber congenital amaurosis: detection of modifier alleles. Invest Ophthalmol Vis Sci. 2005 Sep;46(9):3052-9.

PubMed ID: 
16123401

Perrault I, Rozet JM, Gerber S, Ghazi I, Leowski C, Ducroq D, Souied E, Dufier JL, Munnich A, Kaplan J. Leber congenital amaurosis. Mol Genet Metab. 1999 Oct;68(2):200-8. Review.

PubMed ID: 
10527670

Galvin JA, Fishman GA, Stone EM, Koenekoop RK. Clinical phenotypes in carriers of Leber congenital amaurosis mutations. Ophthalmology. 2005 Feb;112(2):349-56. PubMed PMID: 15691574.

PubMed ID: 
15691574

Sergouniotis PI, Davidson AE, Mackay DS, Li Z, Yang X, Plagnol V, Moore AT, Webster AR. Recessive Mutations in KCNJ13, Encoding an Inwardly Rectifying Potassium Channel Subunit, Cause Leber Congenital Amaurosis. Am J Hum Genet. 2011 Jul 15;89(1):183-90.

PubMed ID: 
21763485

Krabbe Disease

Clinical Characteristics

Ocular Features

Subtle cherry red spots have been reported in one patient.  More than half (53%) have abnormal VEP response but the ERG is normal.  Optic atrophy with blindness is not uncommon but the full ocular phenotype remains unknown.  A 6-month-old male child had MRI T2 evidence of intracranial optic nerve hypertrophy which was attributed to an accumulation of globoid cells.

Systemic Features

There is considerable variation in the time of onset and rate of progression in Krabbe disease, even within families.  Patients with infantile disease may present with symptoms at about 6 months of life, while others are not diagnosed until late childhood or adolescence.  Some evidence of psychomotor retardation is often the first sign of disease with ataxia and limb spasticity soon following.  Irritability is an early sign.  Neurophysiologic studies often show abnormal nerve conduction and this has been documented even in newborns.  The disorder is one of progressive neurodegeneration of both central and peripheral nervous systems leading to weakness, seizures and loss of protective reflexes.  The MRI may reveal T2 hyperintensity in cerebral and cerebellar white matter, internal capsules and pyramidal tracts.  Infection and respiratory failure are responsible for most deaths.

The life-span of Infants with Krabbe disease is approximately one year while those with late-onset disease may not develop symptoms until almost any age and the clinical course is highly variable.

Genetics

This is an autosomal recessive disorder secondary to mutations in the GALC gene (14q31) encoding the enzyme galactosylceramidase, important in the growth and maintenance of myelin.

One patient has been reported with ‘atypical’ Krabbe disease (611722) secondary to a homozygous mutation in the PSAP gene (10q22.1).  The infant had a deficiency of saposin A as well as decreased galactocerebrosidase activity in white blood cells

Treatment Options

Normal blood galactocerebrosidase can be restored and CNS deterioration may be delayed or improved with transplantation of allogeneic hematopoietic stem cells or umbilical cord blood.   However, some patients have residual language deficits and mild to severe delays in motor function.  Results are better if treatment is commenced during infancy before development of symptoms.  These treatments are experimental and long range outcomes remain uncertain.

References

Debs R, Froissart R, Aubourg P, Papeix C, Douillard C, Degos B, Fontaine B, Audoin B, Lacour A, Said G, Vanier MT, Sedel F. Krabbe disease in adults: phenotypic and genotypic update from a series of 11 cases and a review. J Inherit Metab Dis. 2012 Nov 30. [Epub ahead of print]

PubMed ID: 
23197103

Shah S, Freeman E, Wolf V, Murthy S, Lotze T. Teaching NeuroImages:
Intracranial optic nerve enlargement in infantile Krabbe disease. Neurology. 2012
May 15;78(20):e126.

PubMed ID: 
22585439

Siddiqi ZA, Sanders DB, Massey JM. Peripheral neuropathy in Krabbe disease: effect of hematopoietic stem cell transplantation. Neurology. 2006 Jul 25;67(2):268-72.

PubMed ID: 
16864820

Escolar ML, Poe MD, Provenzale JM, Richards KC, Allison J, Wood S, Wenger DA, Pietryga D, Wall D, Champagne M, Morse R, Krivit W, Kurtzberg J. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med. 2005 May 19;352(20):2069-81.

PubMed ID: 
15901860

Hofman KJ, Naidu S, Moser HW, Maumenee IH, Wenger DA. Cherry red spot in association with galactosylceramide-beta-galactosidase deficiency. J Inherit Metab Dis. 1987;10(3):273-4.

PubMed ID: 
3123790