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Familial hydrocephalus
  1. R M CHALMERS,
  2. L ANDREAE,
  3. N W WOOD
  1. University Department of Clinical Neurology (Neurogenetics Section), Institute of Neurology
  2. Department of Surgical Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK
  1. Dr R M Chalmers, University Department of Clinical Neurosciences, Royal Free Hospital School of Medicine, Rowland Hill Sreet, London NW3 2PF, UK. Telephone 0044 171 794 0500 ext 4965; fax 0044 171 431 1577.
  1. R V K DURAI RAJ,
  2. A T H CASEY
  1. University Department of Clinical Neurology (Neurogenetics Section), Institute of Neurology
  2. Department of Surgical Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK
  1. Dr R M Chalmers, University Department of Clinical Neurosciences, Royal Free Hospital School of Medicine, Rowland Hill Sreet, London NW3 2PF, UK. Telephone 0044 171 794 0500 ext 4965; fax 0044 171 431 1577.

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Familial cases of congenital hydrocephalus have often been reported and may result from distinct monogenic disorders or may be multifactorially determined.1 The commonest cause is X linked hydrocephalus associated with stenosis of the aqueduct of Sylvius and, in most families, the genetic basis of this condition is known.2 By contrast, familial adult onset cases are unusual and the genetic basis is unknown.3 We report a family in which the presumed mode of inheritance is autosomal dominant with variable penetrance.

The family pedigree is shown in figure 1. There was no consanguinity.

Patient II-1 was a 76 year old man who presented at the age of 62 years with a 3 year history of progressive gait ataxia, an 18 month history of urinary frequency and occasional urge incontinence, and a 12 month history of cognitive impairment. There was no other medical history of note and he was on no medication. Psychometry showed evidence of a severe and selective verbal memory deficit, impaired attention, and a reduced ability to work at speed, with relative preservation of visual memory, perceptual, and spatial skills. His gait was broad based. Examination of the cranial nerves was normal; there was no disc swelling. There was mild weakness of knee extension bilaterally; reflexes were brisk with flexor plantar responses; there was mild limb ataxia. The remainder of the neurological examination was normal. General examination was normal. Brain CT showed gross communicating hydrocephalus with marked distortion of the fourth ventricle (fig 2). A VP shunt was inserted without perioperative complications; postoperative CT showed some reduction in ventricular size. At review 6 months later his gait and urinary disturbance had largely resolved. Repeat psychometry showed some improvement in his verbal memory and significant improvement in word retrieval skills and ability to work at speed.

Figure 2

CT of patient II-1 showing communicating hydrocephalus.

Patient III-2 was a 47 year woman with a 20 year history of progressive gait disturbance which had been severe for 2 years and an 18 month history of morning headache associated with nausea and vomiting. She reported no cognitive or urinary disturbance. There was no other medical history of note and she was on no medication. Bedside cognitive assessment was normal. Her gait was broad based and spastic. There were saccadic intrusions into pursuit eye movements; examination of the cranial nerves was otherwise normal; there was no disc swelling. Tone was increased in the legs with mild pyramidal pattern weakness, brisk reflexes, and bilateral extensor plantar responses. There was mild limb ataxia. The remainder of the neurological examination was normal. General examination was normal.

Brain MRI showed gross communicating hydrocephalus with marked distortion of the fourth ventricle (fig 3); there was no evidence of a Chiari malformation or other abnormality. Intracranial pressure monitoring showed predominantly normal pressure but intermittent pressure waves. A VP shunt was inserted without perioperative complications. At review 2 months later her gait disturbance had markedly improved and her headache had resolved.

Figure 3

Brain MRI of patient III-2 showing communicating hydrocephalus.

No other family member had any neurological complaints. Patient II-2 (the twin sister of patient II-1 and mother of patient III-2) was reviewed at the age of 75 years. She was asymptomatic and neurological examination was normal. Brain CT showed no evidence of hydrocephalus.

We report on a family containing two members who presented in adult life with gait disturbance and, in one case, urinary symptoms and cognitive decline. Neuroimaging in both cases showed communicating hydrocephalus with marked distortion of the fourth ventricle and each patient gained significant symptomatic benefit from a VP shunt. Although it is possible that this represents a chance association, it seems likely that this family carries a genetic predisposition to the development of communicating hydrocephalus. The presumed mode of inheritance is autosomal dominant with variable penetrance, although X linked inheritance cannot be excluded.

Familial cases of congenital hydrocephalus, both syndromal and non-syndromal, are well described.1 Most cases of X linked hydrocephalus with associated stenosis of the aqueduct of Sylvius are caused by mutations in the gene for neural cell adhesion molecule L1 (L1CAM),2 although some families with otherwise typical X linked aqueduct stenosis do not show linkage to this locus.4 It has been suggested that the aqueduct stenosis seen in this condition may be a secondary phenomenon and that the hydrocephalus begins as a communicating form.5 Mutations of L1CAM are also seen in families with the MASA syndrome (mental retardation, aphasia, spastic paraplegia, adducted thumbs) and spastic paraplegia type 1 (SPG1).6 7 In some other cases of non-syndromal hydrocephalus, autosomal recessive inheritance is suggested by the occurrence of hydrocephalus in siblings of both sexes born to normal but often consanguineous parents.8 One study of 261 pregnancies suggested that, apart from X linked cases, most cases of congenital hydrocephalus were multifactorially determined with a recurrence risk of about 4%.9

We are aware of only one other report of familial adult onset, non-syndromal hydrocephalus.3 This describes two siblings with late onset gait disturbance, urinary frequency, and cognitive impairment. Neuroimaging demonstrated hydrocephalus; intracranial pressure monitoring was not performed. Both cases improved markedly after shunt procedures. Details of the family history of these cases was not provided but it has been assumed that they represent autosomal recessive inheritance. The phenotype of these cases is strikingly similar to the cases we describe and this may support the suggestion that an autosomal locus contributes to the development of apparent “normal pressure” hydrocephalus.

In conclusion, we report the second case of familial adult onset, non-syndromal hydrocephalus. The presumed mode of inheritance is autosomal dominant but further studies will be required before the genetic basis of such cases can be elucidated.

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