Disorder
PCNA-related DNA repair disorder

Clinical Characteristics

General description (for patients):

‘PCNA-related DNA repair disorder’ is an inherited condition which affects how children grow and develop. Individuals with this disorder grow slowly and are smaller than children of a similar age. Children develop difficulties with walking (due to muscle weakness and balance problems), speech and swallowing, which become progressively more noticeable as they grow up. Most will also have learning difficulties, which again may become worse with age.

Individuals with this condition often have hearing difficulties, which may benefit from the use of hearing aids. Their skin is also more sensitive to the sun, which can lead to early skin damage and an appearance of aging prematurely. Patients and families may also notice small red lines on the skin and whites of the eye, which are related to the condition (called telangiectasia). Due to this sun sensitivity, there is an increased risk of developing skin cancers. Individuals with this condition are therefore advised to minimise sunlight exposure and to monitor their skin carefully for any changes.

Medical description (for healthcare providers):

Biallelic pathogenic variants in PCNA result in a neurodegenerative disorder similar to other DNA repair disorders. Cardinal clinical features include neurodegeneration, postnatal growth retardation (-3 to -5.5 SDs), prelingual sensorineural hearing loss (moderate-profound, worse at high frequencies), premature aging, ocular and cutaneous telangiectasia, learning difficulties, photophobia and photosensitivity with evidence of predisposition to sun-induced malignancies.

The neurodegeneration seen in this disorder is characterized by progressive gait instability, muscle weakness, foot deformity, difficulties with speech and swallowing (often resulting in drooling), learning difficulties and cognitive decline with advancing age. By adulthood, wheelchair use may be required and communication may be via gestures only.

Data on brain imaging is limited at present, but atrophy of the cerebellar hemisphere and vermis have been noted, with resultant enlargement of the vermian sulci and widening of the fourth ventricle.

When compared to patients with ataxia telangiectasia, Cockayne syndrome or xeroderma pigmentosa, individuals with PCNA-related DNA repair disorder often have earlier onset hearing loss and a generally milder phenotype, with absence of immunodeficiency and oculomotor apraxia (common in AT).

Genetics:

PCNA-related DNA repair disorder is an autosomal recessive condition caused by a homozygous missense mutation in PCNA on chromosome 20. This gene encodes an essential replication accessory protein that is involved in DNA replication and repair.

To date only five patients have been identified with this condition, all whom originate from the Amish community and have the condition due to the same homozygous pathogenic variant NM_002592.2 c.683G>T; (p.Ser228Ile). It is possible that variants in PCNA which result in a more severe outcome on the protein’s function would not be compatible with life.

Management:

There is no known cure for this disorder. Management is largely supportive and symptom driven. Patients should undergo regular hearing assessments and may benefit from the use of hearing aids. Mobility and neurological features should be monitored, and supportive physiotherapy, occupational therapy and mobility aids utilised as required.

Speech and language therapy may also be beneficial for patients with swallowing and speech difficulties as the disorder progresses.

Individuals should also take precautions to minimise exposure to ultraviolet/sun light, including reducing time spent in direct sunlight, covering exposed skin and utilising high factor sun block on exposed areas. Skin should be carefully monitored for any changes that may represent dermatological malignancy and a low threshold for referral for tertiary dermatological review should be maintained.

Prognosis:

PCNA-related DNA repair disorder is a neurodegenerative condition, with a progressive but variable decline in cognitive, speech and motor skills. Due to the relatively small number of individuals identified with this condition to date, it is difficult to ascertain the full spectrum of symptom severity and speed of progression. However, the eldest reported patient with this disorder (aged 31) communicated via gestures and utilised a wheelchair for mobility.

References:

Baple EL, Chambers H, Cross HE, Fawcett H, Nakazawa Y, Chioza BA, Harlalka GV, Mansour S, Sreekantan-Nair A, Patton MA, Muggenthaler M, Rich P, Wagner K, Coblentz R, Stein CK, Last JI, Taylor AM, Jackson AP, Ogi T, Lehmann AR, Green CM, Crosby AH. Hypomorphic PCNA mutation underlies a human DNA repair disorder. J Clin Invest. 2014 Jul;124(7):3137-46. PMID: 24911150

Moldovan GL, Pfander B, Jentsch S. PCNA, the maestro of the replication fork. Cell. 2007 May 18;129(4):665-79. PMID: 17512402