nystagmus

GM1 Gangliosidosis

Clinical Characteristics
Ocular Features: 

Based on clinical manifestations, three types have been described: type I or infantile form, type II or late-infantile/juvenile form, and type III or adult/chronic form but all are due to mutations in the same gene.  Only the infantile form has the typical cherry red spot in the macula but is present in only about 50% of infants.  The corneal clouding is due to intracellular accumulations of mucopolysaccharides in corneal epithelium and keratan sulfate in keratocytes.  Retinal ganglion cells also have accumulations of gangliosides.  Decreased acuity, nystagmus, strabismus and retinal hemorrhages have been described. 

Systemic Features: 

Infants with type I disease are usually hypotonic from birth but develop spasticity, psychomotor retardation, and hyperreflexia within 6 months.  Early death from cardiopulmonary disease or infection is common.  Hepatomegaly, coarse facial features, brachydactyly, and cardiomyopathy with valvular dysfunction are common.  Dermal melanocytosis has also been described in infants in a pattern some have called Mongolian spots.  Skeletal dysplasia is a feature and often leads to vertebral deformities and scoliosis.  The ears are often large and low-set, the nasal bridge is depressed, the tongue is enlarged and frontal bossing is often striking.  Hirsutism, coarse skin, short digits, and inguinal hernias are common.

The juvenile form, type II, has a later onset with psychomotor deterioration, seizures and skeletal changes apparent between 7 and 36 months and death in childhood.  Visceral involvement and cherry-red spots are usually not present. 

Type III, or adult form, is manifest later in the first decade or even sometime by the 4th decade.  Symptoms and signs are more localized.  Neurological signs are evident as dystonia or speech and gait difficulties.  Dementia, parkinsonian signs, and extrapyramidal disease are late features.  No hepatosplenomegaly, facial dysmorphism, or cherry red spots are present in most individuals. Lifespan may be normal in this type. 

Genetics

This is an autosomal recessive lysosomal storage disease secondary to a mutations in GLB1 (3p21.33).  It is allelic to Morquio B disease (MPS IVB) (253010).  The mutations in the beta-galactosidase-1 gene result in intracellular accumulation of GM1 ganglioside, keratan sulfate, and oligosaccharides.  The production of the enzyme varies among different mutations likely accounting for the clinical heterogeneity. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment that effectively alters the disease course. 

References
Article Title: 

Cone-Rod Dystrophies, X-Linked

Clinical Characteristics
Ocular Features: 

Three X-linked forms of progressive cone-rod dystrophies each with mutations in different genes have been identified.  Central vision is often lost in the second or third decades of life but photophobia is usually noted before vision loss.  Cones are primarily involved but rod degeneration occurs over time.  The ERG reveals defective photopic responses early followed by a decrease in rod responses.   All three types are rare disorders affecting primarily males with symptoms of decreased acuity, photophobia, loss of color vision, and myopia.  The color vision defect early is incomplete but progressive cone degeneration eventually leads to achromatopsia.    Peripheral visual fields are usually full until late in the disease when constriction and nightblindness are evident.  The retina may have a tapetal-like sheen.  RPE changes in the macula often give it a granular appearance and there may be a bull's-eye configuration.   Fine nystagmus may be present as well.  The optic nerve often has some pallor beginning temporally.  Carrier females can have some diminished acuity, myopia, RPE changes, and even photophobia but normal color vision and ERG responses at least among younger individuals.

There is considerable variation in the clinical signs and symptoms in the X-linked cone-rod dystrophies among both affected males and heterozygous females.  Visual acuity varies widely and is to some extent age dependent.  Vision can be normal into the fourth and fifth decades but may reach the count fingers level after that. 

Systemic Features: 

None.

Genetics

Mutations in at least 3 genes on the X chromosome cause X-linked cone-rod dystrophy.

CORDX1 (304020) is caused by mutations in an alternative exon 15 (ORG15) of the RPGR gene (Xp11.4) which is also mutant in several forms of X-linked retinitis pigmentosa (300455, 300029).  These disorders are sometimes considered examples of X-linked ocular disease resulting from a primary ciliary dyskinesia (244400).

CORDX2 (300085) is caused by mutations in an unidentified gene at Xq27.  A single family has been reported.

CORDX3 (300476) results from mutations in CACNA1F.  Mutations in the same gene also cause a form of congenital stationary night blindness, CSNB2A (300071).  The latter, however, is a stationary disorder with significant nightblindness and mild dyschromatopsia, often with an adult onset, and is associated with high myopia. Aland Island Eye Disease (300600) is another allelic disorder.   

Pedigree: 
X-linked dominant, father affected
X-linked dominant, mother affected
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

There is no treatment for these dystrophies but red-tinted lenses provide comfort and may sometimes improve acuity to some extent.  Low vision aids can be helpful. 

References
Article Title: 

Blue Cone Monochromacy

Clinical Characteristics
Ocular Features: 

This is usually a stationary cone dysfunction disorder in which the causative mechanism has yet to be worked out.  Typical patients have severe visual impairment from birth and some have pendular nystagmus and photophobia similar to other achromatopsia disorders.  Vision seems to be dependent solely on blue cones and rod photoreceptors.  The ERG always shows relatively normal rod function whereas the cones are usually dysfunctional. 

In some families, however, there is evidence of disease progression with macular RPE changes and myopia.  This has led to the designation of 'cone dystrophy 5' for such cases even though the mutation locus impacts the same cone opsin genes at Xq28 that are implicated in the more typical BCM phenotype.

Systemic Features: 

None.

Genetics

This is an X-linked recessive form of colorblindness in which DNA changes in the vicinity of Xq28 alters the red and green visual pigment cluster genes via recombination or point mutations.  Alternatively, the control locus adjacent to the cluster may be altered.  In either case, the result may be a loss of function of these genes leaving blue-cone monochromacy.

The mutation for cone dystrophy 5 maps to Xq26.1-qter but the locus encompasses the opsin gene complex at Xq28 as well. 

At least a quarter of individuals with blue cone monochromacy, however, do not have mutations in the vicinity of Xq28 suggesting that additional genetic heterogeneity remains.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Low vision aids can be helpful.  Tinted lenses for photophobia allow for greater visual comfort.  A magenta (mixture of red and blue) tint allows for best visual acuity since it protects the rods from saturation while allowing the blue cones to be maximally stimulated. 

References
Article Title: 

X-linked cone dystrophy caused by mutation of the red and green cone opsins

Gardner JC, Webb TR, Kanuga N, Robson AG, Holder GE, Stockman A, Ripamonti C, Ebenezer ND, Ogun O, Devery S, Wright GA, Maher ER, Cheetham ME, Moore AT, Michaelides M, Hardcastle AJ. X-linked cone dystrophy caused by mutation of the red and green cone opsins. Am J Hum Genet. 2010 Jul 9;87(1):26-39.

PubMed ID: 
20579627

Genetic heterogeneity among blue-cone monochromats

Nathans J, Maumenee IH, Zrenner E, Sadowski B, Sharpe LT, Lewis RA, Hansen E, Rosenberg T, Schwartz M, Heckenlively JR, et al. Genetic heterogeneity among blue-cone monochromats. Am J Hum Genet. 1993 Nov;53(5):987-1000.

PubMed ID: 
8213841

Molecular genetics of human blue cone monochromacy

Nathans J, Davenport CM, Maumenee IH, Lewis RA, Hejtmancik JF, Litt M, Lovrien E, Weleber R, Bachynski B, Zwas F, et al. Molecular genetics of human blue cone monochromacy. Science. 1989 Aug 25;245(4920):831-8.

PubMed ID: 
2788922

Colorblindness-Achromatopsia 5

Clinical Characteristics
Ocular Features: 

Poor visual acuity and congenital nystagmus are characteristic of ACHM5 and may be seen in infancy.  Vision loss can be progressive for those who have a milder form of colorblindness or incomplete achromatopsia.  Such patients have a somewhat later onset and may not have nystagmus or photophobia.  Cone responses are usually absent in the ERG whereas rod responses are often normal.  However, in the incomplete form there may be reduced but measureable cone responses.  There may be some reduction in rod responses with disease progression.  Myopia has been found in some patients.  Atrophy of the RPE in the posterior pole characteristic of progressive cone dystrophies may be seen. 

Systemic Features: 

No systemic abnormalities are found in this disorder. 

Genetics

This is an autosomal recessive disorder resulting from mutations in the PDE6C gene located at 10q24.  This condition is sometimes called cone dystrophy 4.

Other forms of achromatopsia are ACHM3 caused by mutations in CNGB3 (262300), ACHM2 caused by mutations in CNGA3 (216900), and ACHM4 by mutations in GNAT2 (139340).

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the cone dystrophy but dark glasses and red colored contact lenses are helpful in reducing the photophobia and can improve acuity to some extent.  Low vision aids can also be helpful. 

References
Article Title: 

A Nonsense Mutation in PDE6H Causes Autosomal-Recessive Incomplete Achromatopsia

Kohl S, Coppieters F, Meire F, Schaich S, Roosing S, Brennenstuhl C, Bolz S, van Genderen MM, Riemslag FC; the European Retinal Disease Consortium, Lukowski R, den Hollander AI, Cremers FP, De Baere E, Hoyng CB, Wissinger B. A Nonsense Mutation in PDE6H Causes Autosomal-Recessive Incomplete Achromatopsia. Am J Hum Genet. 2012 Sep 7; 91(3) :527-32.

PubMed ID: 
22901948

Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders

Thiadens AA, den Hollander AI, Roosing S, Nabuurs SB, Zekveld-Vroon RC, Collin RW, De Baere E, Koenekoop RK, van Schooneveld MJ, Strom TM, van Lith-Verhoeven JJ, Lotery AJ, van Moll-Ramirez N, Leroy BP, van den Born LI, Hoyng CB, Cremers FP, Klaver CC. Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders. Am J Hum Genet. 2009 Aug;85(2):240-7.

PubMed ID: 
19615668

Colorblindness-Achromatopsia 4

Clinical Characteristics
Ocular Features: 

The ocular phenotype in ACHM4 is similar to that of other forms of achromatopsia.  Nystagmus, poor visual acuity, photophobia, and defects in color vision are usually present.  Some subjects, however, retain some color discrimination, a condition referred to as incomplete achromatopsia.  The ERG documents the absence of cone function but normal rod responses.  The retina appears normal clinically.

Few families have been reported and the complete phenotype remains undocumented.  For example, it has been reported that visual acuity weakens with age in some patients although it is uncertain if this is true of all cases. 

Systemic Features: 

No systemic abnormalities are associated. 

Genetics

This is an autosomal recessive disorder caused by mutations in GNAT2 located at 1p13.  These mutations account for less than 2% of achromatopsia cases.  The majority are caused by mutations in CNGA3 (25%), responsible for ACHM2 (216900) and CNGB3 (50%), causing ACHM3 (262300).  Mutations in PDE6C (613093 ) causing ACHM5 are responsible for less than 2%. No doubt others will be found as many cases do not have mutations in these genes. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder but tinted lenses and low vision aids can be helpful.  Red contact lenses can reduce the photophobia and may improve vision. 

References
Article Title: 

Colorblindness-Achromatopsia 2

Clinical Characteristics
Ocular Features: 

Patients with this congenital, nonprogressive condition often have nystagmus as infants which may improve later. Eccentric fixation secondary to a small central scotoma is often present.  Visual acuity is 20/200 or worse.  Hyperopia is common.  Photophobia is extreme and vision under daylight conditions improves in dim light.  Patients are unable to distinguish any colors.  However, there is considerable variability in symptoms and some individuals retain some color perception and have better visual acuity (sometimes 20/80) than others suggesting some residual cone function.  The term ‘incomplete achromatopsia’ is sometimes applied to such cases but the molecular basis for this variation is unknown.  Optical coherence tomography reveals the central retina to be thinner than in normal controls.  The fundus appearance is normal, however.

ERG responses indicate an absence of cone function with no photopic responses. 

Systemic Features: 

There are no associated systemic abnormalities. 

Genetics

Mutations in CNGA3 account for approximately 25% of cases of achromatopsia.  ACHM2 is an autosomal recessive disorder caused by mutations in CNGA3 (2q11).  Mutations in this gene also have been found in rare patients with progressive cone dystrophies.  A clinically similar but genetically distinct disorder, ACHM3, results from mutations in CNGB3 (262300).  Mutations in GNAT2 (ACHM4; 139340) and PDE6C (ACHM5; 613093) also cause achromatopsia. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the underlying condition but darkly tinted lenses can help in bright light.  Red contact lenses can alleviate photophobia and improve vision as well.  Low vision aids and vocational training can be of great benefit.  In spite of the poor vision, some patients may find that correction of the hyperopia enables them to see better. 

References
Article Title: 

Colorblindness-Achromatopsia 3

Clinical Characteristics
Ocular Features: 

Achromatopsia 3 is a congenital, nonprogressive form of blindness.  It is sometimes referred to as a rod monochromacy or stationary cone dystrophy.  Symptoms are usually present at birth or shortly thereafter.  Patients have pendular nystagmus, progressive lens opacities, severe photophobia, 'day' blindness, and, of course, color blindness.  High myopia is a feature in some populations.  Vision in daylight is often 20/200 or less but vision in dim light is somewhat better. The central scotoma often leads to eccentric fixation. 

The ERG shows a complete absence of cone function.  Optical coherence tomography has demonstrated a reduction in macular volume and thickness of the central retina, most marked in the foveolar region, presumably due in some way to the absence or dysfunction of cone photoreceptors.  Few histologic studies of adequately preserved retina have been reported but those available suggest dysmorphism of cones in the central macula.  The clinical appearance of the retina is usually normal. 

Systemic Features: 

There are no associated systemic abnormalities. 

Genetics

This is an autosomal recessive form of color blindness caused by mutations in CNGB3 (8q21-q22).  This mutation is found in nearly half of patients with achromatopsia.  It is especially common among Pingelapese islanders of the Pacific Caroline Islands where consanguinity occurs frequently due to the founder effect resulting from a 1775 typhoon.  A progressive cone dystrophy has been found in a few patients with mutations in this gene.

Other achromatopsia mutations are in CNGA3 causing ACHM2 (216900), GNAT2 causing ACHM4 (139340), and PDE6C causing ACHM5 (613093).   

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available but darkly tinted lenses can alleviate much of the photophobia.  Low vision aids and vocational training should be offered.  Refractive errors should, of course, be corrected and periodic examinations are especially important in children. 

References
Article Title: 

The cone dysfunction syndromes

Michaelides M, Hunt DM, Moore AT. The cone dysfunction syndromes. Br J Ophthalmol. 2004 Feb;88(2):291-7. Review.

PubMed ID: 
14736794

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 at least 18 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 19 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

LCA 18                  608133                 6p21.1                 PRPH2***

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 PRPH2 (RDS) has also been reported to cause retinitis pigmentosa 7, choroidal dystrophy, and vitelliform macular dystrophy (179605) among others.

See also Leber Congenital Amaurosis with Early-Onset Deafness.

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

Pedigree: 
Autosomal recessive
Treatment
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
Article Title: 

Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease

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

A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement

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

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

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

Effect of gene therapy on visual function in Leber's congenital amaurosis

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

Leber congenital amaurosis

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

Pelizeaus-Merzbacher Disease

Clinical Characteristics
Ocular Features: 

Nystagmus is the major ocular feature in this disease and may appear as early as the first weeks of life in severe cases.  However, more mildly affected individuals may never have nystagmus and, further, it can disappear later.  The ocular movements are usually pendular but may have horizontal and rotatory components as well.  The presence of nystagmus is diagnostically important as it is an uncommon finding in other leukodystrophies.

Systemic Features: 

The classic disease is infantile in onset with hypotonia, titubation, weakness, stridor, respiratory problems, and even seizures often noted in the first weeks of life.   Ataxia, spasticity and cognitive delay are soon apparent.  Infants affected early and severely may never achieve normal motor or mental milestones whereas those less severely affected may at some point ambulate and acquire some language skills.  However, acquired skills may be lost by adolescence.  Survival to the sixth decade of life is common but those with the most severe form of disease may not live beyond the second decade. 

This is an X-linked recessive disorder in which only males have the complete syndrome.  However, multiple carrier females have been studied and many have subtle evidence of disease mainly in gait and motor control.

Genetics

Pelizeaus-Merzbacher disease is the result of mutations in an X-linked gene PLP1 (Xq22).  It is inherited in an X-linked recessive pattern.  Duplication of the PLP1 gene is more common than point mutations.  The signs and symptoms are not diagnostic of PMD as mutations in other genes can cause a similar phenotype. 

Spastic paraplegia-2 (SPG2; 312920)is an allelic disorder in which nystagmus and optic atrophy are also found in some patients.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

There is no effective treatment for this disease.  Airway protection and seizure control should be applied in specific situations.  Patients often need a feeding tube for adequate nutrition.

References
Article Title: 

Pantothenate Kinase-Associated Neurodegeneration

Clinical Characteristics
Ocular Features: 

Clinically evident retinal degeneration is present in a significant number (25-50%) of individuals.  However, when combined with ERG evidence the proportion rises to 68%.  When present it occurs early and one series reported that it is unlikely to appear later if it was not present early in the course of the neurodegeneration.  Some patients have a fleck-like retinopathy.  Optic atrophy may be present in advanced cases.

Systemic Features: 

This is a disorder primarily of the basal ganglia resulting from progressive damage secondary to iron accumulation.  There is an early onset classic form with symptoms of extrapyramidal disease beginning in the first decade of life and rapid progression to loss of ambulation in about 15 years.  Others with atypical disease may not have symptoms until the second or third decades.  Clumsiness, gait disturbance, and difficulty with tasks requiring fine motor coordination are common presenting symptoms.  Motor tics are often seen.  Dysarthria, dystonia, rigidity and corticospinal signs are often present early as well.  Swallowing difficulties may be severe sometimes leading to malnutrition.  Cognitive decline and psychiatric disturbances such as obsessive-compulsive behavior and depression may follow.  Independent ambulation is lost in the majority of patients within one to two decades.    Brain MRIs show an ‘eye of the tiger’ sign with a specific T2- weighted pattern of hyperintensity within the medial globus pallidus and the substantia nigra pars reticulata.

Genetics

Iron accumulation in the basal ganglia resulting from homozygous mutations in the PANK2 gene (20p13-12.3) encoding a pantothenate kinase leads to the classic form of this autosomal recessive disorder. 

This is the most common of several diseases of neurodegeneration with iron accumulation in the brain known collectively as NBIAs.  The group is genetically heterogeneous with many overlapping features.  Mutations in PLA2G6 cause NBIA2A (256600) and NBIA2B (610217) while mutations in a FLT gene cause NBIA3 (606159). The latter does not have apparent eye signs.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Pharmacologic treatment is aimed at alleviation of specific symptoms such as dystonia and spasticity.  Some symptoms may improve with deep brain stimulation.

References
Article Title: 

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