Sir, We read with interest the paper by Jinnah et al. (2010) in the March 2010 issue of Brain, describing the clinical characteristics of a large series of patients with an attenuated variant of Lesch–Nyhan disease. All of the patients reported had either a deficiency of hypoxanthine–guanine phosphoribosyltransferase (HPRT) or a mutation in the HPRT gene, and all had evidence of overproduction of uric acid; but neurological involvement was highly variable and none exhibited the self injurious behaviour that is diagnostic of the full-blown condition.
The existence of a clinically variable phenotype highlights the importance of considering the condition in the differential diagnosis of atypical neurological presentations in adults as well as children, particularly when they are associated with raised levels of serum and/or urinary uric acid. It also opens new possibilities for retrospective diagnosis of historical figures for which detailed medical information exists but has proved difficult to interpret.
A historical case that is of active interest to us is that of King James VI/I (1566–1625), whose medical data we have been examining in the light of earlier claims that he (and others in the same lineage) suffered from variegate porphyria (Macalpine et al., 1968). This claim was based largely on his physical and psychological characteristics, documented in detail in the report of his clinical examination by the leading contemporary physician Sir Theodore Mayerne (1573–655) (Trevor-Roper, 2006). [The full (Latin) text of de Mayerne’s report is available from the British Library: Sloane, 1679, folio 42.]
King James suffered delayed motor development and lifelong difficulties with walking; his speech was said to be abnormal and he experienced swallowing difficulties; he was described as having been clumsy and restless (Beasley, 1995), the latter description perhaps indicating the presence of a movement disorder. He was prone to bouts of intense melancholy and to unpredictable outbursts of anger. King James died at the age of 59 after a period of cognitive impairment and at least one stroke-like episode (Holmes, 2003). These neurological features occurred in the context of: (i) classical symptoms of renal colic, dysuria, haematuria and a sandy appearance to the urine; and (ii) symptoms of arthritis with features of gout. In keeping with usual practice of the time, a post-mortem examination was performed. Its findings, which survive in contemporary correspondence, provide unequivocal evidence of friable urinary calculi, chronic renal disease, cerebral infarction and congestive cardiac failure (Keynes, 1966).
We recently tested the ‘porphyria hypothesis’ using the powerful neurological diagnostic database SimulConsult (http://www.simulconsult.com) (see also Segal, 2007). (SimulConsult is a free online facility that provides a weighted differential diagnosis according to key clinical features. We are grateful to its author, Dr M. Segal, for his advice on using SimulConsult in the case of King James.) The following clinical features were selected from the findings available in the database (we did not include the mood instability or dystonia referred to above, as these are speculative interpretations of non-specific observations): The differential diagnosis returned by SimulConsult is reproduced in Fig.1. The leading diagnosis to emerge was one of the mild variant Lesch–Nyhan disease; none of the porphyrias was listed.
Present with onset ∼1 year old: motor developmental delay (motor retardation, psychomotor).
Present with onset ∼40 years old: renal (kidney) stones (urolithiasis, nephrolithiasis, nephrocalcinosis; crystalluria included).
Present now onset unknown: speech abnormal sound character (dysarthria, slurred, dysphasia, dysphonia, hypophonia, voice nasal, disarticulation, vocal cord paralysis, pseudobulbar palsy included); joint-specific pain or tenderness (arthralgia, arthritis included).
We recognize the absence, from the combination of clinical and metabolic features, of both self-injurious behaviour and intellectual impairment (James’s reputation is that he was intellectually gifted) (Willson, 1956), but the data from Jinnah et al. (2010) confirm that a lack of these features need not rule out an inherited disorder of uric acid metabolism as the underlying diagnosis. Knowledge of the genetic basis of diseases often leads to recognition of wider phenotypes, and this process is enhanced by the availability of searchable electronic databases. The usefulness of SimulConsult in this unconventional context illustrates, however, its potential importance to historians as well as clinicians.