6. Optic nerve

Gene

Optic atrophy 1 (OPA1)

Mutational spectrum

OPA1 is a 29-exon gene that is ubiquitously expressed. A range of

mutations has been described including frameshifts, nonsense and

missense mutations.

Effect of mutation

OPA1 encodes a dynamin-related protein that is thought to be

essential in the maintenance of mtDNA. OPA1 is localized to the

mitochondrion. It is hypothesized that mutations result in altered

function and alteration in the cellular distribution of mitochondria

throughout the cell. To date, there is little evidence of genotype-

phenotype correlation, and no obvious phenotypic differences

between missense and deletion mutations.

Diagnosis

Clinical evaluation; penetrance is said to be 98%. However,

molecular analysis suggests that this may be considerably

lower in some families.

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MIM

535000; 516003 (NADH dehydrogenase, subunit 4); 516000

(NADH dehydrogenase, subunit 1); 516006 (NADH

dehydrogenase, subunit 6)

Clinical features

Ocular

Patients with LHON present with acute or subacute painless central

visual loss in mid-life. In the acute phase fundoscopic examination

reveals peripapillary telangiectasia, disc swelling (which does not

leak on fluorescein angiography) and vascular tortuosity. Optic nerve

damage leads to optic atrophy, particularly temporal, and

development of a centrocecal scotoma. Amongst family members

peripapillary telangiectasia and vascular tortuosity may be seen in

asymptomatic maternal relatives. However, the predictive value of

such findings in mutation carriers is unclear.

Progression and outcome of LHON is variable with a final visual

acuity ranging from 20/40 to no light perception. There are no

clinical predictors of outcome or recovery.

Extraocular

Visual loss is the primary, and generally only, clinical manifestation

in most Leber pedigrees, however, cardiac conduction defects have

been noted in some families. Amongst Finnish and Japanese

patients, pre-excitation syndromes such as Wolff-Parkinson-White

and Lown-Ganong-Levine are common. The nucleotide position (np)

11778 mutation has been associated with multiple sclerosis in

some families and occasional individuals have been described with a

more generalized neurodegenerative picture. It is not clear to what

extent other mtDNA (mitochondrial DNA) changes might contribute

to this picture.

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Leber hereditary optic neuropathy

Age of onset

The mean age of onset is around 30 years in men but is later in

women; the range is 1–70 years. The eyes can be affected

simultaneously or sequentially with an average interval of about two

months. Visual deterioration can range from acute, complete loss to

a progressive decline over 2 years; mean progression time is around

3.7 months.

Inheritance and

LHON is caused by mutations in mtDNA and is only inherited from

population genetics

the ovum. If all the mitochondria contain the same mutant form of

mtDNA then the chances of a female passing this form on to her

children is 100%. However, some individuals carry both mutant and

normal forms of mtDNA—this is termed heteroplasmy. In

heteroplasmic individuals the proportion of mutant to normal DNA

passed to each egg, and hence each child, is unpredictable. During

development the proportion of mutant to normal DNA passed to

each cell or tissue is also unpredictable. Such variabilities in the

level of mutant mitochondria lead to phenotypic variability.

Many individuals represent isolated cases. The proportion of patients

with family histories varies from <50% for np 11778, to 78% for

np 3460. Families homoplasmic for these common mutations

generally exhibit reduced penetrance, with the percentage of

affected relatives in np 11778 families ranging from 33–60%, for np

3460 from 14–40% and for np 14484 from 27–80%.

Chromosomal location

Mitochondrial DNA: a 16569 bp closed circular loop of DNA found

within the mitochondria. It encodes a number of proteins that are

important in the electron transport chain.

Genes and mutational

Defects in a number of the mitochondrial subunits have been

spectrum

associated with LHON. Of these, there are three mtDNA mutations

that definitely cause the disease as they are found in patients but

never in healthy subjects.

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These are designated by the np of the mutation within mtDNA:

• 11778 mutation (np 11778): NADH dehydrogenase, subunit 4

(complex 1, subunit 4; ND4)

• 3460 mutation (np 3460): NADH dehydrogenase, subunit 1

(complex 1, subunit 1; ND1)

• 14484 mutation (np 14484): NADH dehydrogenase, subunit 6

(complex 1, subunit 6, ND6)

ND4, ND1 and ND6 are three of the seven mtDNA encoded

subunits of respiratory complex I (NADH:ubiquinone

oxidoreductase), which accepts electrons from NADH and transfers

them to ubiquinone. The energy released is used to pump protons

across the mitochondrial inner membrane.

There is a great deal of literature about the effects of other mtDNA

variants on the likelihood of developing symptoms. As there is high

variation in mtDNA it is difficult to define the exact significance of

many mtDNA variations and whether a given DNA alteration causes

the disorder or predisposes to the development of symptoms.

Effect of mutation

Mutations in complex 1 are likely to cause a defect in the electron

transport chain. It is not clear why this should affect males more

than females, cause an isolated optic neuropathy or develop acutely

in adult life.

There is evidence for phenotypic correlation amongst these

mitochondrial mutations. The most severely impaired np 11778

patients may lose light perception. By comparison the most severely

impaired np 3460 patients retain light perception and np 14484

patients retain the ability to count fingers.

While males are affected more than females (in the UK 80–90% of

sufferers are males, compared with 60–90% in Japan), the proportion

of males differs for the different mutations: 80% of np 11778,

33–66% of np 3460, and 68% of np 14484 mutations are in males.

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Leber hereditary optic neuropathy

The probability of visual recovery varies between mutations: 4% of

np 11778 patients show some recovery an average of 36 months

after onset. By contrast, 22% of np 3460 patients and 37% of

np 14484 patients show significant recovery within 4–18 months.

Diagnosis and

Clinical history and examination. The majority of other investigations

counselling issues

(e.g. B12) will be normal. If the diagnosis is suspected, mtDNA

testing is now possible as a clinical service. Worldwide, around 90%

of patients carry one of the three primary mutations.

LHON is a devastating disorder and the etiology is poorly

understood. Homoplasmic females (i.e. those with only mutant

mtDNA) are certain to pass on an abnormal gene. This is unusual for

an inherited disorder and is a fact that many patients find hard to

cope with. However, the chance of a child developing visual

symptoms is much lower.

While genetic testing is available and is useful as a diagnostic and

prognostic tool, its utility in counselling the extended family is

uncertain. It should not be used indiscriminately. For those found to

carry mutant mtDNA, there is no way to alter the likelihood of

developing symptoms. Furthermore, testing may carry deleterious

psychological consequences, while the implications for future

insurability are uncertain.

The probability of developing symptoms for mutation carriers is not

100%, one Australian study proposed that the risk of visual loss for

males with the np 11778 mutation is 20% and for females is 4%.

The risks may vary for different mutations, as well as the likelihood

of recovery and final visual outcome.

Risk factors are also poorly understood. There have been

anecdotal reports that smoking, recreational drug use/abuse,

stress and excessive alcohol abuse may contribute to the

development of symptoms, but there is no substantial evidence to

back up these claims.

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MIM

120330; 167409 (PAX2)

Clinical features

Ocular

Optic nerve colobomas are the most common ocular manifestation,

with a high degree of heterogeneity both within, and between,

families and variable functional effect. Optic discs may be normal in

some, while in more severe cases optic nerve abnormalities include

optic nerve hypoplasia/aplasia and morning glory syndrome. Only

one patient has been described with a retinal coloboma, suggesting

that non-optic nerve coloboma are uncommon in ONCR.

Extraocular

Renal abnormalities are the most common non-ocular features.

These are variable and include vesicoureteric reflux, renal

hypoplasia (or even unilateral aplasia), renal tubular atrophy,

glomerulosclerosis and proteinuria. Mutation carriers who are

relatives of severely affected patients may have no detectable

abnormalities. Of 21 patients with proven PAX2 mutations,

10 had end-stage renal failure.

Some patients have neurosensory hearing loss, while developmental

delay is occasionally described in association with microcephaly.

Age of onset

Ocular abnormalities are congenital. Renal abnormalities, while they

may have a congenital aspect (e.g. renal aplasia/hypoplasia) are

progressive. Renal dysfunction often presents in the first decade.

Inheritance

Autosomal dominant

Chromosomal location

10q24.1–q25.1

Gene

Paired box gene 2 (PAX2)

194

Renal-coloboma syndrome

Mutational spectrum

The majority of mutations result in premature protein termination.

Missense mutations within the conserved-paired domain are also

described. A sequence of six G-residues in exon 2 is an apparent

‘hot spot’ for mutation.

Effect of mutation

Haploinsufficiency. As in many conditions associated with

haploinsufficiency, there is a high degree of variability of phenotype.

Diagnosis

Clinical. PAX2 mutations are extremely rare in patients with isolated

optic nerve colobomata.

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195

Including: optic nerve hypoplasia (ONH)

MIM

182230; 165550 (ONH); 601802 (HESX1)

196

Septo-optic dysplasia

Clinical features

Both SOD and ONH are developmental abnormalities that are

generally sporadic. In a very small number of cases they have been

shown to be familial.

Patients with bilateral severe ONH present with early onset of poor

vision associated with roving eye movements (nystagmus). The disc

is small and may have a pale halo and a characteristic double ring.

However, there is a range of severity and ONH may present with

lesser visual problems or, in asymmetrical cases, with unilateral

visual reduction. SOD is characterized by ONH in association with

absence of the septum pellucidum. Midline neurodevelopmental

abnormalities may also include agenesis of the corpus callosum.

Endocrinologic investigations may demonstrate growth hormone,

ACTH and ADH deficiencies, and even panhypopituitarism. Patients

with apparently isolated ONH, including those with normal cerebral

imaging studies, may have endocrinologic evidence of pituitary

dysfunction and, therefore, require appropriate investigation.

Age of onset

Congenital

Inheritance

Sporadic. A small number of autosomal recessive cases have been

described. There is one report of dominant ONH.

Chromosomal location

3p21.2–21.1 (autosomal recessive form)

Gene

Homeobox gene expressed in ES cells (HESX1); alternative name:

Rathke pouch homeobox (RPX).

Mutational spectrum

A homozygous missense mutation within the homeodomain of

HESX1 has been described in consanguineous siblings with SOD. In

addition a small number of individuals with SOD, have been found to

have heterozygous mutations. Such heterozygous mutations

demonstrate incomplete penetrance and variable expressivity.

Effect of mutation

HESX1 is a developmental transcription factor. Expression is high in

the developing forebrain, in particular in Rathke’s pouch, the

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197

primordium of the anterior pituitary, and in the developing anterior

pituitary. Mouse mutants lacking HESX1 have variable defects that

resemble SOD.

The mutant form of the protein fails to bind to the target DNA

sequences that are bound by the normal protein. This suggests that

the mutation causes loss of function.

Diagnosis

Clinical. Cases of ONH, both unilateral and bilateral, should be

investigated for evidence of structural brain abnormalities and

endocrinologic disturbance. Growth should be carefully monitored

during the first years of life. Familial cases are extremely rare and the

condition is not generally regarded as inherited; recurrence risks are,

therefore, low.

198

Septo-optic dysplasia

MIM

222300

Clinical features

Ocular

Progressive optic atrophy presents during childhood. The majority of

patients have a visual acuity of 6/60 or less. Nystagmus may be

present in those with cerebellar degeneration.

Extraocular

Juvenile diabetes mellitus and optic atrophy often develop during

childhood. Diabetes insipidus is a more variable feature (present in

70–75% of patients). Neurosensory deafness develops in around

two-thirds of patients, while other neurological features (e.g. urinary

tract atony, ataxia, peripheral neuropathy and mental retardation)

are common.

WFS is characterized by a progressive neurodegeneration. Many

patients have episodes of psychiatric disturbance including severe

depression and psychosis.

Age of onset

Diabetes is often the first feature, developing in the first decade.

Optic atrophy is noted towards the end of the first decade or the

beginning of teenage years.

Epidemiology

The estimated prevalence in the UK is <1:700,000.

Inheritance

Autosomal recessive

Chromosomal location

4p16.1 (WFS1); 4q22–q24 (WFS2, linkage only)

Gene

Wolframin (WFS1)

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Mutational spectrum

WFS1 mutations include premature protein truncating mutations

and missense mutations. There are no clear-cut genotype-phenotype

correlations. Mutations are distributed throughout the gene.

Effect of mutation

WFS1 is a transmembrane protein, its function is unclear although it

is hypothesized to be important in islet cell and neuronal survival.

Diagnosis

Diabetes insipidus is difficult to diagnose due to problems with fluid

restriction in patients with diabetes mellitus. A high index of

suspicion is required for patients with optic atrophy and diabetes

mellitus. Mutation testing of WFS1 is only available on a research

basis at present.

200

Wolfram syndrome