Familial hypokalemic periodic paralysis hypoPP

Most of the early original publications on periodic paralysis were probably describing hypoPP, as this is the commonest form of periodic paralysis. Talbott published an extensive review of the literature on periodic paralysis in 1941 (Talbott, 1941). This paper summarized many of the characteristic features of periodic paralysis including age of onset, male predilection, development of fixed weakness and provoking factors. Talbott cites Musgrave's interesting observation from 1727 of a 21-year-old woman who presented with attacks of weakness, and suggests this may be the first description of periodic paralysis (Musgrave, 1727). However, some of the features in Musgrave's original case were atypical, including loss of speech and attacks always occurring on the same day of the week. From the beginning of the 19th century a number of reports started to appear describing cases of sporadic periodic paralysis and the first familial case of an affected father and son was reported by Shakhnowitsch in 1882. Early hypotheses on the patho-genesis of periodic paralysis included the theory of muscle ischemia as the underlying pathology (Westphal, 1885; Holtzapple, 1905; Schmidt, 1919; Mankowsky, 1929). Goldflam (Goldflam, 1890) and others (Crafts,

Correspondence to: Dr. M.G. Hanna, Centre for Neuromuscular Disease, National Hospital for Neurology and Neurosurgery, University College London Foundation NHS Trust, and Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK. E-mail: [email protected], Tel: +44-(0)207-837-3611, Fax: +44-(0)207-6921-2085.

1900; Singer and Goodbody, 1901) suggested that an autotoxin was responsible. Hartwig (1874) was the first to describe electrical inexcitability of muscles during an attack of paralysis. Indeed, Hartwig was so surprised by the lack of response to electrical stimulation that he initially thought that his apparatus was malfunctioning. Bie-mond and Daniels (1934) provided the first report of low potassium levels during a spontaneous attack. This was confirmed in another case a year later when Walker (1935) reported convincing evidence that there was a 50% decrease of serum potassium during an attack.

It is now known that hypoPP is the most common form of familial periodic paralysis with a prevalence of 0.4-1:100 000 in Europe (Kantola and Tarssanen, 1992; Fontaine, 1994). The inheritance is autosomal dominant with reduced penetrance in women giving a male:female ratio of ~3:1 (Elbaz et al., 1995).

There are currently three genes implicated in familial hypoPP including CACNA1S, SCN4A and KCNJ2. Mutations in the voltage-gated calcium channel gene CACNA1S account for the majority of cases (~70%; Fouad et al., 1997; Miller et al., 2004). In less than 10% of cases mutations in the voltage-gated sodium channel gene SCN4A are reported (Bulman et al., 1999; Davies et al., 2001; Sternberg et al., 2001; Miller et al., 2004). Mutations in KCNJ2 encoding an inward-rectifying potassium channel can cause Andersen-Tawil syndrome (Plaster et al., 2001). Since this condition is distinct and can present with both hypo- and hyperkalemic periodic paralysis it will be discussed separately. A mutation in KCNE3 reported as pathogenic in hypoPP was later found to be a benign polymorphism

(Abbott et al., 2001; Sternberg et al., 2003; Jurkat-Rott and Lehmann-Horn, 2004).

Hypokalemic periodic paralysis generally presents later than hyperkalemic paralysis, usually between the ages of 5 and 20, typically in the teenage years (Fouad et al., 1997; Miller et al., 2004; see Table 4.1). However, onset over the age of 20 has been reported (Miller et al., 2004). Attacks tend to last from several hours up to 2-3 days. It is often difficult for patients to give a precise estimate of attack duration as both onset and resolution tend to be gradual. A sudden onset of weakness leading to a collapse would argue against a diagnosis of periodic paralysis. It is generally considered that in hypoPP attacks are longer and more severe than in hyperPP. Although this is our experience, a recent retrospective study did not confirm this. It is possible the use of medication by patients in the study may have influenced attack duration (Miller et al., 2004).

In a typical hypoPP episode the patient wakes in the night or in the morning with generalized severe weakness being "unable to move". Often intake of a carbohydrate-rich meal or strenuous exercise the preceding day or night can be identified as a triggering factor. Focal episodes of weakness may be triggered by exercise only involving one limb but are more common in hyperPP. Tendon reflexes are diminished or absent. Even in a severe attack cranial muscles are spared so that speech and eye opening remain intact. Impairment of speech, visual symptoms or alterations in consciousness are not expected and should trigger consideration of other diagnostic possibilities. Respiratory muscles are mostly spared but a reduction in vital capacity and consequent

Table 4.1

Clinical features of hyperkalemic periodic paralysis and hypokalemic periodic paralysis

Hyperkalemic periodic paralysis

Hypokalemic periodic paralysis

Onset of symptoms Triggers

Time of attack Duration of attack Severity of attack Additional symptoms Serum potassium Interictal electromyography Treatment

Gene/ion channel

First decade

Rest after exercise, cold, fasting, potassium-rich food Any time of the day Minutes to hours Mild to moderate, may be focal Myotonia or paramyotonia Usually high, may be normal Myotonic discharges in some, positive

McManis test Acetazolamide, dichlorphenamide, thiazide, beta-agonist SCN4A: Nav1.4 (sodium channel subunit), KCNJ2: Kir2.1 (potassium channel subunit)

Second decade

Rest after exercise, carbohydrate load

Typically when waking up in the morning

Hours to days

Moderate to severe

Never myotonic discharges, positive McManis test

Acetazolamide, dichlorphenamide, potassium supplementation, potassium-sparing diuretics

CACNA1S: Cav1.1 (calcium channel subunit), SCN4A: Nav1.4 (sodium channel subunit), KCNJ2: Kir2.1 (potassium channel subunit)

respiratory failure has rarely been reported to occur in severe attacks (Ziegler and McQuarrie, 1952; Rowley and Kliman, 1960; Resnick and Engel, 1967). Strength gradually improves over the course of the next day or two although some patients indicate that it takes up to a week to recover. Even when the patient is not complaining of clear clinical attacks careful quantitative strength measurement has suggested that there is diurnal variation of muscle power, being lowest in the early hours of the morning and highest in the afternoon and evening (Engel et al., 1965). Attacks often become less frequent and severe in later life and in common with hyperPP a permanent myopathy may develop (Biemond and Daniels, 1934). Interestingly fixed weakness has been described to occur even in patients without a strong history of frequent paralytic attacks (Sternberg et al., 2001). For example, in some females the late-onset myopathy may be the only manifestation without any clinically evident paralytic attacks (Links et al., 1990). A study of a large kindred with hypoPP showed that nearly all subjects over the age of 50 years had evidence of fixed muscle weakness (Links et al., 1994). It remains unproven whether active treatment to reduce the frequency of paralytic attacks might reduce the development of fixed weakness later.

A useful feature to distinguish between hypo- and hyperkalemic periodic paralysis clinically is the absence of (true) myotonia in hypoPP. The only exception to this rule so far is the SCN4A mutation P1158S which has been described in a Japanese kindred causing myotonia and cold-induced hypoPP (Sugiura et al., 2000). Previously in the literature only a single case was reported with myotonia and periodic paralysis where the potassium level was low (1.9 mEq/l) during the attack. However the patient was from a family with typical myotonic dystrophy and the precise diagnosis is unclear (Leyburn and Walton, 1960). There are a handful of other reports of apparent clinical myotonia (mostly myotonic lid lag) in association with hypokalemic periodic paralysis (Odor et al., 1967; Resnick et al., 1967; Griggs et al., 1970). Here the explanation may be that the lid lag was not due to true electrical myoto-nia, which explains why no EMG myotonia could be demonstrated in any of these patients. Although lid lag is a sensitive marker of myotonia it does not appear to be very specific as it has been found even in healthy volunteers (Odor et al., 1967) and should therefore be interpreted with caution.

A number of factors may induce or exacerbate attacks. These include ingestion of carbohydrates, administration of insulin and epinephrine injections (Ziegler and McQuarrie, 1952; Rowley and Kliman, 1960; Engel et al., 1965). Stress and excitement and exposure to cold are also often listed by patients as triggers (Miller et al.,

2004). Menstruation and pregnancy have been reported to cause an increase in frequency and severity of attacks (Bender, 1936; Links et al., 1994).

Although serum potassium levels are often reduced, especially at the beginning of an attack, they may not be below the normal range. The original studies of periodic paralysis in the early 20th century reported a number of other electrolyte changes (for review see Talbott 1941), including a decrease in serum phosphate in parallel with potassium and reduced urinary excretion of sodium, potassium, chloride and water. Serum creatine kinase (CK) may be normal or slightly elevated in between attacks. During paralytic attacks there can be a moderate rise in CK (De Keyser et al., 1987).

Electrocardiogram (ECG) changes have been observed with very low potassium including prominent U waves, flattening of T waves and ST depression. Inter-ictal ECG is usually normal although affected members of a kindred with hypokalemic periodic paralysis carrying the R528H CACNA1S mutation were reported to suffer from cardiac arrhythmias (Fouad et al., 1997). The presence of prominent U waves, frequent ventricular ectopic beats or arrhythmias should alert the clinician to the possibility of Andersen-Tawil syndrome (ATS) (see later section). Familial hypokalemic periodic paralysis is not associated with clinical or echocardiographic evidence of cardiomyopathy (Schipperheyn et al., 1978).

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