8. Metabolic disorders

214

Genetics for Ophthalmologists

MIM

301500

Clinical features

Fabry disease is an X-linked inborn error of glycolipid metabolism

caused by deficiency of the lysosomal enzyme a-galactosidase A

(GLA). Diagnosis is often delayed, but the ocular features are

characteristic. Patients have an increased risk of renal and cardiac

disease and reduced life expectancy.

Ocular

Although characteristic, ocular manifestations are not usually visually

significant. Cornea verticillata, similar to that seen with various drugs

such as amiodarone, is seen in both affected males and the majority

of female carriers. Wedge-shaped anterior lens opacities, as well as

branching spoke-like opacities, are seen in around one-third of

patients. Tortuosity of the retinal and conjunctival vessels is common.

Neurological

Debilitating episodes of pain (Fabry crises or acroparesthesiae)

begin in childhood, lasting hours or sometimes days. These often

affect the peripheries and may be excruciating. Abdominal or flank

pain is also common.

Skin

Small blue-purple telangiectatic lesions (angiokeratomas) are seen

in childhood, in particular over the buttocks and umbilical region.

They increase in number with age.

Vascular

Cardiac abnormalities are common and may cause premature death;

left ventricular hypertrophy, mitral valve disease and conduction

defects have been described. Cerebral vascular disease is common

Metabolic disorders

215

and may lead to infarction. Avascular necrosis of the femur or talus

head may lead to pain or a limp.

Renal

Proteinuria is common, and end-stage renal failure is a frequent

cause of premature death in the second to fourth decades.

Age of onset

Although symptoms may begin in childhood, diagnosis is often

delayed until the third or fourth decades.

Inheritance

X-linked

Gene

Galactosidase alpha (GLA)

Chromosomal location

Xq22

Mutational spectrum

Around 160 mutations have been described. Over 50% are missense

changes found throughout the gene. However, nonsense, splice-site

and small deletions or insertions have also been described.

Effect of mutation

Mutations result in abolition of enzyme activity. A number of

patients with some residual activity have an atypical cardiac form

of Fabry disease. Mutations cause progressive deposition of the

glycosphingolipids in the endothelium of blood vessels (the major

pathological feature) and in the kidneys.

Diagnosis

Due to the non-specific nature of early symptoms, diagnosis is often

delayed. Fabry disease is associated with premature death (mean

age <45 years) as a result of renal, cardiac and cerebrovascular

complications. The ocular features are characteristic and may be

diagnostic. Diagnosis may be confirmed by GLA estimation in WBC

or fibroblasts, which is used as the basis of prenatal diagnosis on

CVS or amniocytes. While the majority of carriers may be detected

clinically (e.g. by ophthalmic examination), DNA diagnosis is now

available through certain centers and may also be used as a means

of prenatal diagnosis.

216

Fabry disease

galactokinase activity levels. Accumulation of osmotically active

compounds within the lens is thought to lead to cataract formation.

Diagnosis

If suspected, diagnosis can be made on urinalysis demonstrating

the presence of a non-glucose reducing substance. There is absent

galactokinase activity in red blood cells.

218

Galactokinase deficiency

MIM

230400

Clinical features

The most common features are failure to thrive, associated with

jaundice, hypotonia and lethargy. Vomiting and diarrhea begins

within days of initiating milk ingestion, and jaundice occurs within

the first few weeks after birth due to unconjugated hyperbilirubinemia.

Hepatomegaly and abnormal liver function develops after prolonged

exposure to unlimited quantities of milk and if left untreated will

progress to cirrhosis. There is an increased rate of neonatal death

as a result of E. coli sepsis, perhaps because of reduced leukocyte

bactericidal activity (galactosemia is one of the differential diagnoses

in neonates with E. coli sepsis).

Lens changes may be observed on slit-lamp examination within a

few days of birth. There is an ‘oil-droplet sign’ in the red reflex due

to the increased refractive index of the lens nucleus. It is thought

that this is due to accumulation of osmotically active sugar alcohols

(e.g. galactitol) in the lens leading to water influx. This phenomenon

is reversible by strict dietary control, without which permanent lens

opacity develops. Regular ophthalmic follow-up is required even in

the presence of good dietary control.

Dietary therapy does not preclude long-term consequences. A

reduction in IQ is observed in the majority of patients, even with

apparently good dietary control. Severe delay is uncommon but

delayed speech and verbal dyspraxia are common as are visuo-

spatial, mathematical and attention span difficulties. Almost all

females have primary ovarian failure due to hypergonadotrophic

hypogonadism. However, prospective dietary therapy prevents other

complications such as cataract, liver disease and E. coli sepsis.

Metabolic disorders

219

Galactosemia cataract: this lens opacity had cleared substantially in the few days

of dietary therapy between diagnosis and examination—the ‘oil droplet’

is visible inferiorly.

Age of onset

Within days of birth and the onset of milk feeding. Lens changes

may be present within 1–2 weeks.

Epidemiology

Estimates show significant variation from country to country—the

prevalence at birth is estimated to be 1:70,000 in the UK and

1:30,000 in Ireland. In the USA, frequencies vary from 1:35,000

in the state of New York to 1:190,000 in Massachusetts. Carrier

frequencies vary from 0.9–1.25:100.

Inheritance

Autosomal recessive

Chromosomal location

9p13

Gene

Galactose-1-phosphate uridylyl transferase (GALT)

Mutational spectrum

A broad mutational spectrum (>130 mutations) has been recognized

in a wide number of populations; the majority are missense

mutations. Within Caucasian populations, two mutations (Q188R

and K285N) account for >70% of galactosemia-producing alleles,

while in black populations the S135L allele accounts for >60%.

220

Galactosemia

Several common normal variants are recognized, such as the Duarte

variant that is associated with 50% enzyme activity, this has a

population prevalence of around 5–6%.

There may be a phenotypic spectrum associated with the different

alleles between which biochemical differences can be observed (e.g.

the common S135L allele is associated with normal GALT activity

in white blood cells). It is likely that the genotypic heterogeneity

underlies biochemical, as well as phenotypic, variation.

Effect of mutation

GALT catalyzes the conversion of galactose-1-phosphate and

UDP-glucose to glucose-1-phosphate and UDP-galactose. This is

critical to the metabolism of galactose in most organisms. Functional

assays of a variety of mutations have shown that most result in virtual

abolition of enzyme activity. The cause of long-term, diet-independent

complications remains unclear and may be tissue-specific.

Diagnosis

A presumptive diagnosis can be made on urinalysis demonstrating

the presence of a reducing substance—although lactose, fructose

and pentose may all give a similar result. Definitive identification of

galactose may be achieved using paper or gas-liquid chromatography.

Diagnosis is confirmed by means of a biochemical assay of GALT

function in heparinized blood.

Metabolic disorders

221

Including: GM2 gangliosidosis type I, or Tay-Sachs disease

(hexosaminidase A deficiency); GM2 gangliosidosis type II, or

Sandhoff disease (hexosaminidase B deficiency).

MIM

272800 (Tay-Sachs); 268800 (Sandhoff)

Clinical features

The gangliosidoses are a group of inborn errors of sphingolipid

metabolism that result in neuronal accumulation of a glycolipid,

GM1 or GM2 ganglioside.

GM1 gangliosidosis is a rare AR condition occurring as a result of

b-galactosidase deficiency. Children with this deficiency have severe

cerebral degeneration and die by the age of 2 years. The GM2

gangliosidoses, which are also AR conditions, cause lipid (GM2

ganglioside) accumulation in the lysosomes of neurons of the brain,

which results in enlargement of the head due to cerebral gliosis,

progressive neurodegeneration and blindness. Affected children

usually die by the age of 2–4 years.

222

GM2 gangliosidoses

Extraocular

Affected infants generally appear completely normal at birth but

show progressive weakness and loss of motor skills from 3–6

months of age. There is decreased attentiveness and pronounced

extension in response to sound (startle reaction). Progressive

neurodegeneration is associated with seizures and spasticity and

leads to death before the age of 4 years. In Sandhoff disease (type

II), unlike Tay-Sachs (type I), there are coarse features,

hepatosplenomegaly and skeletal abnormalities.

Age of onset

Loss of motor skills occurs in the first year of life. A cherry-red spot is

present in the early stages. There is a range of phenotypes in both

type I and II GM2 gangliosidoses with juvenile (in which symptoms

begin from 2–10 years of age) and adult-onset forms.

Epidemiology

Tay-Sachs disease is present in all populations but is most common

among Ashkenazi Jews (about 1:3600 in Ashkenazi Jewish births

in the USA, with a carrier rate of about 1:30). Among Sephardic

Jews and all non-Jews, the gene frequency is about 100-times less

common. The carrier rate for Sandhoff disease has been estimated

to be 1:500 in Jews and 1:300 in non-Jews.

Inheritance

Autosomal recessive

Chromosomal location

15q23–q24 (HEXA); 5q13 (HEXB)

Metabolic disorders

223

Gene

Hexosaminidase A (HEXA) – Tay-Sachs; hexosaminidase B

(HEXB) – Sandhoff.

Mutational spectrum

Over 70 mutations have been described in HEXA. In the infantile

form, null alleles resulting from frameshifts or premature

terminations are common. Amongst the Ashkenazi Jewish

population, three common mutations account for 90–95% of the

alleles and testing is routinely available. This facilitates diagnostic

and carrier screening.

Two pseudodeficiency alleles resulting from missense alterations

have also been identified. These alleles, when present in the

heterozygous state, result in HEXA enzymatic activity similar to

that of a heterozygote for Tay-Sachs. However, as the allele is not

disease-causing when present with a true null allele this can give

a false indication of carrier status on biochemical testing.

Over 20 mutations have now been described in HEXB, including

missense, nonsense, splicing and deletion mutations. Both juvenile

onset and more attenuated adult forms of Sandhoff disease are

caused by mutations in HEXB.

Effect of mutation

The phenotypic consequences of the majority of mutations occur as

a result of alterations in protein folding and intracellular transport

rather than abolition of enzyme activity.

Hexosaminidase A is a heterodimeric protein comprising an a chain

and a b chain (encoded by HEXA and HEXB genes, respectively).

It cleaves a terminal b-linked N-acetylgalactosamine from GM2

ganglioside. Hexosaminidase B is a homodimeric protein.

HEXA mutations (Tay-Sachs disease) result in reduced levels of

HEXA enzyme activity. HEXB mutations result in reduced levels of

HEXA and HEXB enzyme activity (Sandhoff disease).

Diagnosis

Tay-Sachs disease is one of a number of conditions associated with

a cherry-red spot at the macular. Others include Niemann-Pick

disease type A, a disorder of the metabolism of sphingomyelin—a

224

GM2 gangliosidoses

Metabolic disorders

225

MIM

258870

Gyrate atrophy: fundus periphery of 7-year-old child presenting

with night blindness.

Clinical features

Patients present with night blindness in the first decade of life. There

is a loss of peripheral vision and ultimately central visual function;

90% of patients are highly myopic.

Examination reveals sharply demarcated scalloped areas of

chorioretinal atrophy that are first seen in the periphery and then

spread posteriorly towards the macula. These become confluent

during the second and third decades. Patients develop posterior

subcapsular lens opacities.

Age of onset

Night blindness develops during the first 5 years. By the time

symptoms occur, retinal changes will be apparent.

Inheritance

Autosomal recessive

Chromosomal location

10q26

226

Gyrate atrophy of the choroid and retina

Gene

Ornithine aminotransferase (OAT)

Mutational spectrum

A broad spectrum of mutations within the OAT gene have been

described. These include whole exon deletions that lead to absence

of mRNA, protein truncating mutations and missense mutations.

Effect of mutation

Mutations lead to loss of enzyme function. The mechanism of

progressive retinal degeneration is unknown.

Ornithine is a non-essential amino acid that is metabolized within

the urea cycle and is an important intermediate in the production

of glutamate and proline. It may be produced by metabolism of

dietary arginine. OAT is a mitochondrial matrix enzyme that

converts a-ketoglutarate and ornithine to glutamate and

glutamate-g-semi-aldehyde.

Diagnosis

Diagnosis of the proband relies upon the presence of suggestive

symptomatology and clinical findings. Younger siblings may be

diagnosed on biochemical grounds. High ornithine levels can be

detected in the blood or urine of all patients—OAT activity is absent

or severely reduced.

Gyrate atrophy is one of the few retinal dystrophies for which there

is a potential treatment. In some patients, administration of the

co-enzyme (vitamin B6, pyridoxine) reduces ornithine levels. Long-

term clinical evaluation in humans has been difficult to achieve.

Recently a mouse model of OAT deficiency has been developed that

is characterized by a retinal dystrophy analogous to gyrate atrophy.

In the mouse, a low-arginine diet can help to reduce ornithine levels

and prevent the development of retinal dystrophy. This is strong

evidence to suggest that dietary manipulation, although difficult to

follow, maybe worthwhile for affected children.

Metabolic disorders

227

MIM

236200

Lens subluxation in homocystinuria.

Clinical features

Homocystinuria is an inborn error of metabolism resulting from a

deficiency of cystathionine b-synthase. Clinical manifestations

involve the eye, the CNS, and the skeletal and vascular systems.

Ocular

The major ocular complication of homocystinuria is ectopia lentis.

Classically this is inferior subluxation but it may occur in any

direction. Ectopia lentis is not present at birth but is progressive. It

may be the presenting feature at the age of 3–5 years. It is present in

the majority of patients who are either untreated or do not respond to

medical therapy. Medical therapy reduces its frequency.

Extraocular

Patients with homocystinuria tend to be blond and hypopigmented

presumably because homocystine inhibits the activity of tyrosinase.

228

Homocystinuria

Skeletal

Patients with homocystinuria have a variable Marfanoid habitus with

dolichostenomelia (tall stature and thin body), arachnodactyly, pectus

abnormalities, pes cavus, high-arched palate and kyphoscoliosis.

Patients tend to have stiffness of joints, in contrast to Marfan

syndrome in which patients may have joint laxity.

CNS

Mental retardation is common among untreated patients (>50%);

mean IQ is 50–60 among patients who are unresponsive to

vitamin B6. Seizures and psychoses are common. Intellectual

development is significantly improved by early diagnosis and

medical treatment.

Vascular

Around one-sixth to one-quarter of patients will suffer

thromboembolic events. These may be arterial or venous and may

affect large or small vessels. Patients treated early have significantly

fewer episodes. Treatment involves administration of vitamin

B6 (pyridoxine) or a cofactor of cystathionine b-synthase or, for

those who do not respond, a low methionine diet +/- betaine

supplementation.

Age of onset

Birth. In those countries where neonatal screening occurs

(e.g. Ireland and certain parts of the UK) diagnosis may be early.

Ectopia lentis is usually diagnosed around the age of 3 years.

Epidemiology

Worldwide; incidence is variable and estimated to be

1:300–500,000. It is higher in Ireland.

Inheritance

Autosomal recessive

Chromosomal location

21q22.3

Metabolic disorders

229

Gene

Cystathionine beta synthase (CBS)

Mutational spectrum

The majority of mutations in CBS are missense mutations.

Effect of mutation

CBS catalyzes the conversion of homocystine and serine to

cystathionine. A deficiency of CBS leads to accumulation of

homocystine and methionine in the blood and tissues. Mutations

in the gene have been shown to abolish CBS enzyme activity.

Homocystine metabolism has been implicated in the etiology of

neural tube defects and vascular disease.

Diagnosis

Patients have a positive cyanide-nitroprusside test in fresh urine.

Both urine and plasma levels of homocystine are raised. Molecular

genetic testing is supplemental.

230

Homocystinuria

MIM

204200

Clinical features

The neuronal ceroid lipofuscinoses are a group of recessive disorders

that result in the accumulation of lipopigments throughout the body.

The group includes a number of genetically distinct conditions that,

although related, have quite different clinical courses. Of these

conditions, the juvenile form of Batten disease is most likely to be

seen by the ophthalmologist.

Ocular

Batten disease may first present with symptoms and signs of a

rod-cone dystrophy. Symptoms of night blindness and visual field

constriction may be noted, while on examination there may be ‘salt

and pepper’ changes in the peripheral retina with mild alteration of

macular pigmentation. Children often demonstrate ‘over-looking’

with eccentric fixation above the object of gaze. Occasionally there

may be a bull's-eye maculopathy. With time, classical signs of a

widespread retinal degeneration (disc pallor, vascular attenuation

and peripheral pigmentation), become apparent.

Full-field ERGs demonstrate absent rod responses and severely

reduced cone responses. The retinal degeneration is both severe

and widespread, and shows a rapid progression early in the

disease course.

Extraocular

Batten disease is a fatal neurodegenerative disorder that begins in

childhood. Early symptoms usually appear between the ages of 5 and

10 years. Some patients present with early signs of subtle personality

and behavior change, developmental delay or clumsiness. Over time,

Metabolic disorders

231

affected children suffer mental impairment, psychoses, worsening

seizures and progressive loss of sight and motor skills. Eventually

children become blind, bedridden and demented. Batten disease is

progressive and fatal. Death is usually in the late teens or early 20s,

although some patients may live into their 30s.

Age of onset

Onset is at the age of 5–10 years. Batten disease represents an

important differential diagnosis in previously healthy, normally

sighted children who develop progressive visual failure and retinal

dystrophy at around this age.

Epidemiology

Batten disease and other forms of neuronal ceroid lipofuscinoses are

relatively rare, occurring in an estimated 2–4 of every 100,000

births in the USA. They appear to be more common in Finland,

Sweden, Newfoundland and Canada.

Inheritance

Autosomal recessive

Chromosomal location

16p12.1

Gene

Ceroid lipofuscinosis, neuronal type 3 (CLN3)

Mutational spectrum

Around 70–85% of chromosomes from patients with Batten disease

carry an allele with a 1.02 kb deletion within the gene. This is

predicted to result in the production of a significantly truncated

protein. Other deletion mutations are also described that have a

similar prognosis.

Among patients with other mutations, a small number of missense

changes have been described that affect residues that are conserved

across species and are thought to be crucial to protein function.

These may result in delayed onset or slower progression. In some

individuals, visual deterioration was noted in the first decade of life

but CNS deterioration was delayed for some decades.

232

Juvenile neuronal ceroid lipofuscinosis type 3

Effect of mutation

CLN3 has no known homology to other proteins and its function has

not yet been defined. The protein is highly conserved and has a

homolog in Saccharomyces cerevisiae. Mutations are thought to

severely reduce or abolish enzyme activity. Missense mutations

associated with a milder phenotype may result in some residual

enzyme activity.

Diagnosis

A number of supplementary investigations can support the diagnosis if

there is clinical suspicion of Batten disease. Examination of leukocytes

may demonstrate inclusions, although these are not totally conclusive.

The disorders are characterized by accumulation of autofluorescent

lipopigments in neurons, as well as in other cells of the body to a lesser

extent. These appear as fingerprint inclusions on electron microscopy.

Historically the diagnosis was confirmed by brain, sural nerve or rectal

biopsy. However, it is now possible to detect the characteristic changes

in skin, or even conjunctival tissue biopsy.

Batten disease is a devastating diagnosis in which visual and

intellectual deterioration develop in a formerly healthy individual.

Inevitably, this has enormous consequences throughout the family.

The diagnosis is often made after the birth of younger siblings who

have a 25% risk of being affected.

Metabolic disorders

233

Clinical features

The mucopolysaccharidoses are a group of progressive

disorders characterized by the intralysosomal accumulation of

mucopolysaccharides (glycosaminoglycans). They are classified

into types I–VII.

The MPS have a wide range of severity from profound growth,

developmental retardation and childhood death, to mild

manifestations with normal intelligence and survival to adulthood.

However, some clinical features are common to the whole group:

characteristic coarse facial features with frontal bossing, prognathism

and a depressed nasal bridge, hepatosplenomegaly and skeletal

abnormalities ranging from generalized growth deficiency with

kyphosis to mild joint contractures. In some MPS (e.g. Hurler

syndrome), developmental delay is associated with progressive

neurological deterioration.

MPS

Face

Skeletal

Intellect

Life

Other

Corneal

expectancy

clouding

Hurler (I-H)

Coarse

Short stature;

Profound

Death by 10

Respiratory

+

kyphosis;

retardation

years of age

infections;

contractures

myocardial/

cardiac valve

dysfunction

Scheie (I-S)

Mildly

Contractures

Normal

Normal

Aortic valve

+

coarse

(e.g. of hand)

disease

Morquio

Mildly

Short stature;

Normal

Third to fourth

Cardiac valve

Mild

(IV)

coarse

kyphosis;

decade of life

disease

contractures

Maroteaux-

Coarse

Short stature;

Normal

Second to

Aortic/mitral

+

Lamy (VI)

kyphosis;

third decade

valve disease

contractures

of life

234

Mucopolysaccharidoses

Glaucoma

Early-onset glaucoma, presumed to be secondary to intracellular

mucopolysaccharide accumulation in the anterior chamber drainage

angle, is a rare complication of the MPS.

Age of onset

Diagnosed in the first few years of life, from around 6 months for

severe MPS I, to 5 years in mild cases.

Epidemiology

It is estimated that 1:25,000 births will be affected by one of the

MPS disorders.

Inheritance

Autosomal recessive (MPS I, III, IV, V, VI and VII).

X-linked (MPS II/Hunter syndrome).

Metabolic disorders

235

MPS

MIM

Gene

Chromosome

Enzyme

I (Hurler/Scheie)

252800

IDUA

4p16.3

a-L-iduronidase

II (Hunter)

309900

IDS

Xq28

Iduronate sulfate sulfatase

IVA (Morquio A)

253000

GALNS

16q24.3

Galactosamine-6-sulfate sulfatase

IVB (Morquio B)

253010

GLB1

3

b-galactosidase

VI (Maroteaux-

253200

ARSB

5q13.3

N-acetylgalactosamine-4-sulfatase

The MPS disorders are caused by mutations in a diverse group of

enzymes, which lead to the accumulation of different

mucopolysaccharides. All result from mutations that substantially

reduce or abolish enzyme activity. In the case of Hurler/Scheie

syndrome, caused by mutations in a-L-iduronidase, milder

phenotypes result from mutations that retain residual enzyme activity.

Diagnosis

When suspected clinically, MPS can be detected biochemically by the

presence of elevated urine glycosaminoglycans. Enzyme activity can

be measured in lymphocytes and/or fibroblasts as well as in cultures

of chorionic villi or amniocytes. DNA testing and mutation analysis

offer an alternative method of diagnosis as well as prenatal diagnosis,

although this is not as widely available as biochemical testing.

236

Mucopolysaccharidoses

MIM

219800

Clinical features

Cystinosis is a rare AR lysosomal storage disorder characterized by

elevated levels of intracellular cystine. Tissue damage results from

accumulation of cystine crystals.

Metabolic disorders

237

polydipsia develop later. By 1 year of age there is growth retardation,

rickets and, on biochemical investigation, metabolic acidosis and

increased renal excretion of glucose, phosphate and potassium.

Children fail to thrive and without therapeutic intervention remain

short and underweight. Tubular dysfunction (renal Fanconi

syndrome) develops in the first year progressing to end-stage renal

failure by the age of 9 years on average.

Age of onset

The classic form presents in the first year of life. In late-onset

nephropathic cystinosis (MIM 219900) there are similar signs and

symptoms but of a later onset with the age of presentation ranging

from 2–26 years.

Epidemiology

The incidence is estimated to be 1:50,000.

Inheritance

Autosomal recessive

Chromosomal location

17p13

Gene

Cystinosin (CTNS)

Mutational spectrum

A broad range of mutations have been described, including protein

truncating mutations and missense mutations. A common 57 kb

deletion is found in 75% of European patients.

Effect of mutation

CTNS encodes a lysosomal membrane protein involved in cystine

transport across the lysosomal membrane. Protein truncation

mutations and missense mutations within transmembrane domains

are thought to result in loss of function and cause severe disease.

Mutations having milder effects occur within regions that are

functionally unimportant.

Diagnosis

When suspected clinically, cystinosis can be diagnosed by WBC

cystine determination. This can also be achieved using fibroblast

cultures. Prenatal diagnosis is carried out using amniocentesis or CVS.

238

Nephropathic cystinosis

MIM

266500; 602026 (PHYH)

Clinical features

Refsum disease is a peroxisomal disorder that results in

accumulation of phytanic acid. The characteristic clinical features

are peripheral neuropathy, RP and cerebellar ataxia. Peripheral

neuropathy affects 90% of patients, resulting in both motor and

sensory loss; cerebellar ataxia is present in 75% of patients. In

addition, the majority of patients show electrocardiographic changes

while some have nerve deafness and an ichthyotic skin rash.

The retinal dystrophy in Refsum disease may be the presenting

feature with weakness and loss of balance developing later or being

subtle features at the time of presentation.

Phytanic acid is derived entirely from the diet in dairy products, egg

yolk, some fish, lamb and beef, white bread and boiled potatoes.

Avoidance of these foods will lower its plasma concentration and may

lead to improvement of the peripheral neuropathy and ichthyosis,

although retinal changes are not arrested. Plasmaphoresis may

supplement dietary manipulation if this is ineffective on its own.

An infantile form of Refsum disease has been identified

(MIM 266510) in which there is an early-onset severe retinal

dystrophy associated with dysmorphism, mental retardation,

hepatomegaly and neurosensory hearing loss. Strictly this is a

peroxisomal disorder, although infants with the condition also have

raised levels of phytanic acid.

Age of onset

In classic Refsum disease, night blindness may begin in the second

decade of life or later in adulthood.

Inheritance

Autosomal recessive

Chromosomal location

10pter–p11.2

Metabolic disorders

239

Gene

Phytanoyl-CoA hydroxylase (PHYH)

Mutational spectrum

Missense splicing and frameshift mutations have been described.

Effect of mutation

PHYH is a peroxisomal protein that catalyzes the first step in the

alpha-oxidation of phytanic acid. In vitro assays have shown that

mutations in PHYH result in loss of enzyme activity.

Diagnosis

If Refsum disease is suspected, diagnosis can be confirmed by

demonstrating elevated plasma phytanic acid levels.

240

Refsum disease