Carrell-Krusen Symposium Invited Lecture

Molecular Basis of Genetic Heterogeneity: Role of the Clinical Neurologist Lewis P.

Rowland, MD

ABSTRACT Advances in molecular genetics have disclosed many different explanations for allelic heterogeneity, how different clinical syndromes arise from mutations in the same gene. The converse, how similar clinical syndromes arise from mutations of different genes on different chromosomes is called locus heterogeneity. Both, however, give rise to some disease-defining mutations, as in childhood spinal muscular atrophy or Duchenne muscular dystrophy. Nevertheless, new problems have been created, including what might be called "diagnosis by the number," diverse syndromes from mutations in the same gene without current explanation, or siblings with different clinical syndromes. These discoveries have transformed the clinical neurology of heritable diseases. They also provide clinicians with new responsibilities and opportunities in defining clinical syndromes and influencing the evolution of our clinical language. ( J Child Neurol 1998;13:122-132).

Genes for a few human diseases had been mapped earlier, but positional cloning became a reality in 1983, when the gene for Huntington disease was localized to chromosome 4 by James Gusella and his colleagues. Progress in the nearly two decades since then has created a true revolution in the way we think about heritable diseases. It seems appropriate to step back to appraise the impact of molecular genetics on clinical neurology. I will select some examples and hope to be excused for using so many neuromuscular diseases, the ones that led me to an interest in genetics and have been such fruitful molecular examples. 1 I will also emphasize the reverse; namely, that clinical neurologists have played a major role in gene-mapping, and clinical contributions still play a major role. It is possible to discern some new general principles evolving from molecular genetics in the past two decades. They are especially evident in confronting two overarching questions: (1) how do different clinical syndromes result from mutations within the same gene and gene product? This

Received Dec

2, 1997. Accepted for publication Dec 2, 1997. Department of Neurology, Columbia University College of Physicians and Surgeons; the Neurology Service, Presbyterian Hospital in the City of New York; and the Neurological Institute, Columbia-Presbyterian Medical Center, New York, NY. Address correspondence to Dr Lewis P. Rowland, Neurological Institute, Columbia-Presbyterian Medical Center, New York, NY 10032. From the

122

is allelic heterogeneity; and (2) how do similar clinical syndromes result from mutations in gene products that are encoded on different chromosomes (locus heterogeneity)? The closer we examine these diseases the more we encounter diverse fascinating explanations. The fundamental challenge is this: we do not understand the pathogenesis of any heritable disease, how the mutation distorts normal cellular functions to result in a particular clinical neurologic syndrome. Identification of affected gene products in these diseases, however, tells us what the normal protein must do. The mutations challenge us to understand how the disease comes about, and how we might develop rational

therapy. At least 14 different mechanisms seem to play a role in the different phenotypes that result from allelic heterogeneity (Table 1). I will briefly describe the allelic mechanisms of Xp21 dystrophinopathies and spinal muscular atrophy; pleiotropism or disease-specific mutations in hyperkalemic periodic paralysis and related syndromes; modifying polymorphisms in prion diseases; and position effect variegation in facioscapulohumeral muscular dystrophy. Also, gene dosage and amplification of trinucleotide repeats have become important considerations in allelic heterogeneity. Locus heterogeneity, on the other hand, has helped to explain many diseases, including what seem to be currently little-discussed conditions, such as the separation of scapuloperoneal muscular dystrophy from facioscapulohumeral dystrophy or scapuloperoneal muscular atrophy. Locus

123

Table 1.

mtDNA

=

mitochondrial DNA; tRNA

=

Mechanisms of Allelic

Heterogeneity

transfer RNA.

is evident in the several forms of familial Alzheimer disease but locus homogenity has also unified some syndromes of non-Alzheimer dementias. Locus heterogeneity has outpaced clinical analysis in the classification of spinocerebellar atrophies, hereditary spastic paraplegia, and limb-girdle muscular dystrophy, resulting in classifications by the number-instead of words (Tables 2,

heterogeneity

3, and 4). Clinicians have several roles and opportunities now. They are needed to define syndromes as families are studied for linkage analysis. Clinicians are needed to be certain that clinical data are not discarded (as in debates about hyperkalemic periodic paralysis) or the tendency to rename syndromes by the number (as in hereditary spastic paraplegia or cerebellar ataxias) and to set priorities straight in using eponyms. DYSTROPHINOPATHIES: EXAMPLES OF ALLELIC HETEROGENEITY

disease, also located at Xp2l, dystrophin was the first gene product to be identified as a result of positional cloning. Allelic heterogeneity can explain why syndromes are similar but differ in essentials, but these allelic diseases also raise questions. Duchenne and Becker muscular dystrophies illustrate the point. Both result from mutations in the gene for dystrophin. In Duchenne muscular dystrophy, the protein is, for practical purposes, absent. In Becker muscular dystrophy, the protein is abnormal in size (almost always smaller than normal) and present in reduced amounts. This promatous

found difference is attributed to the nature of the mutation. An &dquo;in-frame&dquo; mutation inserts a stop codon; the resulting truncated protein is vulnerable to degradation and is not available for its normal role in the membrane. An &dquo;out-of-frame&dquo; deletion permits synthesis of a smaller than normal protein in less than normal amounts. Most of the Duchenne mutations are found at either end of the gene and most of the Becker mutations affect the middle rod-like section. Some Puzzles of Allelic

The identification of dystrophin was a landmark in many ways. With the gene and gene product for chronic granuloTable 2.

ADCA

=

autosomal dominant cerebellar ataxia; SCA

pallido-luysal atrophy. *Modified from Rosenberg.76

=

Ophthalmoplegia

spinocerebellar atrophy;

MJD

in

=

Heterogeneity

It is not clear, however, why either Becker or Duchenne disease becomes progressively more severe, or why Becker

Spinocerebellar Degenerations*

Machado-Joseph disease; EOM

=

extraocular movements; DRPLA

=

dentato-rubro-

124

Table 3.

Hereditary Spastic Paraplegia*

Table 4.

Limb-Girdle Muscular

Dystrophies

LGMD = limb-girdle muscular dystrophy; AD autosomal dominant; AR = autosomal recessive; SCARMD = severe childhood autosomal recessive muscular dystrophy; DMD Duchenne muscular dystrophy. =

=

*Data from Fink et al.&dquo; HSP hereditary spastic =

paraplegia.

muscular dystrophy starts later and is less severe.3 Moreover, other allelic mutations of the same gene result in totally different syndromes4: asymptomatic hyperCKemia, myoglobinuria, X-linked cramps and myalgia, congenital muscular

dystrophy, limb-girdle dystrophy,

or

quadriceps myopathy.

How these diverse syndromes arise is not known. Other unanswered questions concern carriers of the mutated dystrophin gene; some are asymptomatic, some have calf hypertrophy as the only manifestation,&dquo; some show high serum levels of creatine kinase,7 and some have an overtly disabling myopathy. Cardiomyopathy may be the dominant manifestation in Becker muscular dystrophy or in a woman carrying the gene.~~9 Perhaps most puzzling are families in which one child has a severe early onset Duchenne form and a sibling has a later Becker-like syndrome.’° This question arises in many heritable diseases and the answer is usually the same vagary-&dquo;a second, modifying gene-or an environmental factor.&dquo; In Xp21 myopathies, however, there may be a propensity to mutations at the Duchenne muscular dystrophy locus, resulting in two different mutations and two different syndromes in the same kindred. 11l

MECHANISMS OF ALLELIC HETEROGENEITY: HOW DIFFERENT SYNDROMES RESULT FROM MUTATIONS IN THE SAME GENE Inherited Prion Diseases

Two clinically different syndromes have been mapped to the same mutation in the gene for the prion protein (PrP). 12 Both familial Creutzfeldt-Jakob disease and familial fatal insomnia result from a mutation at codon 178 in the gene for the prion protein. At codon 129, there is a common polymorphism, a triplet that encodes valine in patients with Creutzfeldt-Jakob disease and methionine in familial fatal insomnia. The power of the polymorphism at position 178 is seen in other ways, too. For instance, transmissible CreutzfeldtJakob disease provides an example of the roles of both gene and environment in delineating a clinical syndrome.

People who are homozygous for methionine at codon 129 are susceptible to iatrogenic Creutzfeldt-Jakob disease transmitted by either the cerebral route (electrodes, dural grafts) or by injections of growth hormone prepared from human pituitary glands. Of Creutzfeldt-Jakob disease cases induced by cerebral transmission, 93% have affected people who were homozygous at codon 129, as were 91% of those who had received growth hormone. 13> 14 Other prion syndromes may also differ clinically and pathologically as a result of the patterns at codon 129. 15 How codon 129 affects the clinical syndromes is not known, but its impact seems

powerful. Spinal Muscular Atrophy of Childhood

or

Adolescence

In other diseases, however, the nature of the clinical variation is more difficult to fathom. For instance, there are three childhood versions of autosomal recessive spinal muscular atrophy. The most severe is the infantile form or Werdnig-Hoffmann disease, which begins before birth and is fatal before age 2 years in more than 80% of cases. The survivors are never able to sit or stand alone. In the least severe form, the children do learn to walk. In an intermediate form (type 2), onset is in early childhood; they can sit but do not walk. Type 3 begins in late childhood, adolescence, or even after age 20 (Kugelberg-Welander syndrome); these individuals walk and many function well for decades. Remarkably, all three map to chromosome 5ql 1.2-13.~~ Almost all studies have shown this linkage to chromosome 5.19,20 In the first report of linkage, two cases were unlinkedzl and there were few other reports of &dquo;unlinked&dquo; families.22 However, in some unlinked cases, the diagnosis could be doubted, 23,24 or there were later reports of technical errors in the linkage study 16 So consistent is the linkage to 5q that Victor Dubowitz25 concluded the clinical diagnosis must be wrong if linkage cannot be demonstrated. Nonlinkage also distinguishes similar but clinically different

disorders.26 The seemingly extreme position of Dubowitz now needs only slight modification because the survival of motor neuron (SMN) gene has been found to be deleted in 95% to 99% of patients with any of the three major formsz7 and even in a rare type of infantile-onset with congenital heart disease. 21 The reliability of this association provides a DNA test for prenatal diagnosis.29 Several patients who lacked the deletion

125

found to have a point mutation in the SMN gene. Even spinal muscular atrophy beginning after age 20 years shows were

deletions of both

exons

7 and 8 of the SMN

gene.&dquo;&dquo; In one

family, a frameshift mutation in exon 3 reinforced the view that the SMN gene is responsible for the disease31 and other point mutations implicate SMN as the responsible gene.&dquo;’ However, as many as 18% of patients with type III lack a deletion..34 Failure to find a deletion in some cases has been attributed to gene conversion.35 Normally there are two only slightly different copies of the gene, one telomeric (SMNt), the other centromeric (SMNc). If there is a conversion from the telomeric to the centromeric gene, SMNt will seem to have been deleted but there will be extra copies of SMN c. :3G-39 At first, indirect methods were used in attempts to relate size of deletion to clinical severity. If neighboring genes were deleted in addition to the SMN gene, the deletion was larger. One of the neighboring genes is the neuronal apoptosis inhibitory protein (NAIP), which is deleted in 50% of type 1 patients; one is called p44,4° and there are others.4~ In general, clinical severity does parallel the size of the deletion, 42-46 as determined by deletions of the neighboring genes in addition to the SMN gene. More specific data were provided when expression of SMN gene in brain and spinal cord was found to be predominantly neuronal, and primarily in motor neurons of the ventral horns.47 Immunocytochemical studies of the gene product, the SMNc protein, in postmortem spinal cord or liver, or in lymphoblastoid cells showed severe depletion in type 1 patients, less severe in type 1 and much less in type 3. These findings imply a loss of function of the gene product, which seems to be involved in RNA metabolism.48-50 The diagnostic specificity of an SMN gene deletion is high. In one study, no deletion was found in children with neurogenic arthrogryposis with bone fractures, spinal muscular atrophy with respiratory failure before apparent limb weakness, or spinal muscular atrophy with olivopontocerebellar atrophy. Also, no deletions of SMN gene were found in the neuronal form of Charcot-Marie-Tooth disease,51 distal spinal muscular atroph y, 52 or amyotrophic lateral sclerosis. 53 One child had a complex congenital syndrome of limb weakness, facial diplegia, respiratory failure, and ophthalmoplegia, with histologic evidence of axonal sensorimotor neuropathy; the large size of the SMN gene deletion suggested that additional genes contributed to the atypical and severe syndromes4 in this and another child with widespread neuronal changes.&dquo; In one study, a deletion was found in two of four patients with arthrogryposis.56 The diagnostic specificity of deletions in SMN gene is therefore very high. Nevertheless, there are families in which one sibling is mildly affected and another severely. 17-61 In some families, some patients show early childhood onset and some begin in adult years.&dquo; Asymptomatic family members may show the same deletion,°~-°4 suggesting the action of modifying

genes. 46

The current diagnostic version of the Dubowitz Rule can be stated as follows: if, in a suspected case of spinal muscular atrophy, a deletion of the SMN gene is found, the diagnosis is secure. If there is no deletion, there may be a point mutation or some other disease may be responsible. In atypical cases or in asymptomatic relatives of patients with spinal muscular atrophy, the presence of a deletion in SMN gene suggests the action of a modifying gene or environmental factors. DELINEATION OF DISEASES BY DNA ANALYSIS

Molecular genetics changes clinical neurology in many ways. One striking example is the resolution of ancient clinical debates. We have already alluded to the relationship between Duchenne and Becker muscular dystrophies, long suspected but impossible to define on clinical grounds. There were other rewards as still other Xp21 syndromes were

delineated, including cramp syndromes, myoglobinuria, congenital muscular dystrophy. Soon after, there was evidence of genetic heterogeneity-syndromes that are similar clinically but prove to be soon

and

linked to different genes on different chromosomes. At that

time, we learned that other severe muscular dystrophies of childhood showed no abnormality of dystrophin. That led to the search for other genes and other gene products, and the sarcoglycans were discovered by Kevin Campbell and his colleagues.65 Simultaneously, different forms of dystrophin-normal childhood dystrophies were mapped to the genes for these proteins. As a result we have witnessed a rapidly changing nomenclature; we have gone from words to numbers. Terminology has skipped from the vividly expressive term &dquo;severe childhood autosomal recessive muscular dystrophy (SCARMD)&dquo; to &dquo;adhalinopathy&dquo;66 (from the original Arabic name of the protein that has since become &dquo;sarcoglycan&dquo;) and then to a list of limb-girdle dystrophies without clinical names; instead they are listed by number or the name of the gene productG7,G8 (Table 4). Neither approach will enhance the ability of clinicians to recognize the specific disease. Instead, the identification of a childhood myopathy (or even one of adults) in an individual patient will go unassigned until the laboratory report appears to give the results of DNA analysis or immunocytochemical identification of the gene product in a muscle

biopsy. The enumeration of limb-girdle muscular dystrophies (LGMDs) is based mostly on the recognition of related cytoskeletal proteins that are essential for normal function of the sarcolemma .69 The dystrophin-associated glycoproteins include some that are extracellular (merosin, formerly called laminin) and dystroglycans, some that are located on the cytoplasmic side of the muscle plasma membrane (dystrophin, syntrophin, and utrophin), and some that span the surface membrane (sarcoglycans). The importance of these glycoproteins (sarcoglycans and dystroglycans) is emphasized by the dystrophin-normal dystrophies.7° In these conditions, one of sarcoglycans is

126

Table 5.

Amino acids:

’&dquo;Adapted

Arg

=

arginine; Ser

=

Mutations of MPZ

serine; Cys

=

cysteine; Leu

=

(Po) and Clinical Phenotype of Charcot-Marie-Tooth Syndromes*

leucine; Gly

=

glycine; Gin

=

glutamine.

from Warner et al.89

All but one of these newly recognized diseaseassociated proteins is part of the muscle cytoskeleton; the exception is calpain,’1 a muscle-specific calcium-activated protease. However, some families show no linkage to any of these loci; identified mutations account for about 10% of all myopathies with normal dystrophin.72 As a group, these &dquo;limb-girdle muscular dystrophies&dquo; exemplify locus heterogeneity. The &dquo;sarcoglycanopathies&dquo; teach us that dystrophin is needed to anchor the sarcoglycans, but the glycoproteins are important themselves and seem to function as a complex. If a key sarcoglycan is missing, dystrophin does not function properly. More, mutation of one sarcoglycan leads to secondary loss of the other components of the complex. Terminology now encompasses these as

missing.

sarcoglycanopathies. 7~-&dquo;5 Parallel problems of nomenclature (with numbers replacing words) have arisen in classifying spinocerebellar

degenerations7(j (Table 2) and hereditary spastic paraplegia7? (Table 3), with locus heterogeneity providing the engine and clarifying relations between syndromes that are slightly different on clinical grounds. 18 We now recognize identification of the mutation as a requisite for clinical diagnosis,&dquo; not only in spinal muscular atrophy and Xp21 diseases. Among the diseases so defined are scapuloperoneal muscular dystrophy, Miyoshi type distal myopathy, oculopharyngeal muscular dystrophy, and oculodistal myopathy. Charcot-Marie-Tooth Diseases These conditions were recognized as being clinically heterogeneous for many years before the impact of molecular genetics. Locus heterogeneity was soon established by linkage, with two forms of slow-conduction neuropathy (CMT1A and 1B) linked to chromosome 17 (most families) or chromosome 1 (few families). Then the gene product for the chromosome 17 type was identified as peripheral myelin protein 22 (PMP22). Soon, there was evidence that the resulting clinical syndromes depended in part on gene dosage, as proposed by Lupskig°e81 and Chance82 and their colleagues. The normal genotype contains two copies of the gene for PMP22. As they described the findings, the common mutation is a duplication of the gene on one chromosome, or three copies of the gene. An individual who was homozygous for the CMT1A duplication (four copies of the gene) was affected more severely than the heterozygous parent or sibling in the same family; the severe form could be comparable to the severe neuropathy

of Dejerine-Sottas disease. If there is a deletion of one CMT1A gene, leaving a single copy of the gene, the resulting syndrome is that of hereditary neuropathy with liability to pressure palsies (HNPP). There are still no reports of a human double deletion (no gene copies), but transgenic mice lacking PMP22 showed hypermyelination and demyeli-

nating peripheral neuropathy, myelin degeneration comparable to the human disease.83.84 Similar dosage effects are seen with the gene for peripheral myelin sub-zero (Po or PMZ), including PMZ-deficient mice 15 and CMT1B. Shapiro et all analyzed the crystal structure of the extracellular domain of the PMZ protein. The findings help to explain how the molecule normally functions in the adhesion of the myelin layers to form networks of molecules. Warner et all&dquo; proposed that the specific mutation may determine the clinical syndrome (Table 5). Nonsense mutations at positions 125 and 152 were associated with the CMT1B phenotype, with resulting truncated proteins that do not reach the membrane. This loss-of-function probably also applies to histidine and serine substitutions at position 69, which may disrupt the interaction between PMZ proteins. In one family, both parents were heterozygous and had CMT1B; their homozygous child had the Dejerine-Sottas disease. As a consequence of these discoveries, DNA diagnosis is now essential for proper genetic counseling. CharcotMarie-Tooth disease therefore shows the effects of locus heterogeneity, gene dosage, and specific mutations. Understanding the molecular structure of the gene product permits deductions about the pathogenesis of particular clinical syndromes. Also, identification of the gene product led Harding8? to propose a classification that includes genetic, electrophysiologic, and clinical data.

Table 6. Syndromes Associated with Duplication of PMP22 at Chromosome 17p11.2*

*Modified fromThomas

et

al.10

’&dquo;Plus&dquo; signs 2

implies additional evidence of central nervous system disease (pyramidal patients, pyramidal plus cerebellar 1 patient), diaphragm affected (3 including 1 with fecal incontinence), cramps (1), monoclonal paraproteinemia (1), diabetes mellitus (1).).

or

127

Despite these disease-defining mutations and evidence of locus heterogeneity, there is also problematic allelic heterogeneity, as exemplified by the diverse syndromes seen with PMP229° or Po duplications87 and variation of clinical disorders in members of the same family with identical mutations’&dquo; (Table 6). Locus heterogeneity is manifest by the continuing recognition of new hereditary neuropathy syndromes, 92,93 while CMT6 (with optic atrophy) and other long known syndromes have not yet been mapped.94 Hyperkalemic Periodic Paralysis and Paramyotonia Congenita: Disease-Specific Mutations or a Pleiotropic Disease?

.

.

’

,

For decades there had been debate among clinicians about relationship of hyperkalemic periodic paralysis and paramyotonia congenita. As long ago as 1958, Drager, Hammill, and Sh y95 concluded that these entities were variants of a single disorder, both being seen in the same family. Similar families continue to be described.91 In 1991, several groups of investigators mapped both diseases to the same locus on chromosome 17 and the gene product was identified as the sodium channel a-subunit. It might have been expected that this congruence would prove the identity of the two syndromes. Instead the view emerged that, although the two syndromes are allelic, disease-specific mutations within the gene encode pure hyperkalemic periodic paralysis and others, paramyotonia congenita. 97 I have wondered where the investigators found the families of pure paramyotonia congenita needed for these studies, because that disorder is so rarely seen in a muscle clinic. On reviewing the literature, I found that the two North American studies98,99 were based on three families in which at least one person had had a spontaneous attack of paralysis 100-102 in addition to symptomatic myotonia. In the study of families in Germany, however, paramyotonia was said to be transmitted as a pure syndrome 1°~ and those families were not described in detail. Only one individual in the North American families was challenged with potassium. Instead of disease-specific mutations, there could be another view of the problem. In 1967, the investigative issue was to separate hyperkalemic from hypokalemic periodic

the

paralysis. Layzer

et all&dquo; examined 12 of 35 affected indi-

viduals from four

families; in each family an attack was precipitated by potassium in at least one person. Among the 12, 6 had both symptomatic myotonia and spontaneous attacks of paralysis; 3 had myotonic symptoms with no prior attack of paralysis (conforming to paramyotonia congenita), and 3 had had neither myotonic symptoms nor attacks of paralysis but myotonia was found on clinical examination (also conforming to paramyotonia, if not challenged with potassium). Hyperkalemic periodic paralysis could be a pleiotropic syndrome, manifest by myotonia, periodic paralysis, cold sensitivity, and potassium sensitivity. The predominance of one or another manifestation is determined by the particular mutation, the influence of other genes, or environ-

mental alterations of potassium metabolism. Similar problems arise in the analysis of myotonic muscular dystrophy and the Schwartz-Jampel syndrome, which are also

pleiotropic disorders. Cannon 105 has gone even further, suggesting that still other disorders are also part of the hyperkalemic periodic

paralysis-paramyotonia congenita complex, including myotonia fluctuans, potassium-aggravated myotonia, normokalemic periodic paralysis, and acetazolamide-responsive myotonia congenita. Non-Alzheimer Dementias

Cerebral autosomal dominant arteriopathy, subcortical infarcts, leucoencephalopathy (CADASIL), is already in the category of diseases defined by gene mapping, even though the locus was identified as late as 1993.1°° The condition is recognized clinically by onset before age 40 years of recurrent subcortical infarcts or transient ischemic attacks, followed by progressive dementia and, ultimately, spastic quadriplegia, and pseudobulbar palsy. 107 Magnetic resonance imaging (MRI) shows the leucoencephalopathyl°8 and brain biopsyl°9 can demonstrate the unidentified material deposited in the walls of meningeal arteries, with no evidence of amyloidosis or atherosclerosis. Linkage to chromosome 19q12 confirms the diagnosis. The same locus encodes the gene for familial complicated migrainell° and migraine is encountered often in CADASIL kindreds. In one family, however, a syndrome clinically similar to CADASIL was not linked to chromosome 19,111 giving evidence of locus heterogeneity. Moreover, another nonCADASIL meningeal arteriopathy has been described with &dquo;granular cortical atrophy&dquo; 112 and was related to cases reported earlier as having &dquo;familial Binswanger’s disease&dquo; or &dquo;thromboarteritis obliterans (Buerger’s disease).&dquo; That syndrome differed from CADASIL clinically because there was a family history of parkinsonism and because the index case also had autopsy-proven amyotrophic lateral sclerosis; neither parkinsonism nor amyotrophy has been reported with CADASIL. James Goldman and Arthur P Hays (personal communication, 1997) re-studied the pathology of that case after the description of CADASIL; they deemed the arteriopathy different because the arterial walls lacked the deposits seen in CADASIL and the distribution of small infarcts also differed. Only identification of the mutations and affected gene products will determine the relationship of these two conditions. Mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS) is one of the main causes of stroke before age 40 years113 and new syndromes continue to be recognized. 114 Chromosome 17-linked dementia; Wilhelmsen-Lynch syndrome; and disinhibition, dementia, parkinsonism, amyotrophy complex (DDPAC) are terms used to describe another entity. Lynch et all 15 described a family with these features and localized the gene to chromosome 17. The clinical features form a unique combination and the pathology is distinct in showing ballooned neurons and

128

Table 7.

Wilhelmsen-Lynch Syndrome:

Chromosome 17-Linked

Dementia, Parkinsonism,Amyotrophy; Related Diseases orAllelic

Heterogeneity?

the Ricker syndrome. It could be considered muscular dystrophy type 2.&dquo;lz9

&dquo;myotonic

Scapuloperoneal Muscular Dystrophy For decades there has been debate about the syndromes subsumed with this name. Clinically, the disorder resembles

neuronal inclusion. 116 Several other syndromes (with different names) have shown linkage to the same locus&dquo;’-&dquo;9 and others are expected (Table 7). Other Diseases Defined

by Linkage

or

Lack of Linkage

Potassium-Sensitive Hyperkalemic Periodic Paralysis with Cardiac

Arrhythmia

1967, Klein et all&dquo; described a syndrome of childhood periodic paralysis, which they considered normokalemic. Soon, Lisak et all recognized lingual myotonia in one patient and suspected hyperkalemic periodic paralysis; an attack was precipitated by administration of potassium. An additional case was reported by Gould et all&dquo; who noted dysmorphic facial structures and cited Andersen as having described a similar case. Then Ptacek, Johnson, and Griggsl2;3 named the disorder &dquo;Andersen’s syndrome&dquo; to emphasize the dysmorphic features. Rowland 124 objected to this designation on grounds that Andersen et al 115 had not recognized any role of potassium in the syndrome; he also noted that spontaneous attacks might be normokalemic, hyperkalemic, or even hypokalemic, as found in some families with hyperkalemic periodic paralysis. Nevertheless, potassium-sensitivity was characteristic in almost all reported cases challenged with potassium. Sansone et al 126 have found no linkage to either the hyperkalemic periodic paralysis, long QT syndrome, or calcium-channel loci, establishing this as an independent disorder. They emphasized the inconsistency of serum potassium levels during spontaneous attacks, at times high, low, or normal. In

Ricker

Syndrome

This is a condition that clinically resembles myotonic muscular dystrophy, but differs in showing proximal rather than distal limb weakness and calf hypertrophy in some patients. 111,1211 The distribution of weakness led to the acronym PROMM (proximal myotonic myopathy). Myotonia is more difficult to discern than in myotonic muscular dystrophy and was found in only 63% of the 35 patients studied by Ricker et al. 127,128 Muscle wasting is not seen and some show calf hypertrophy. Cataracts and baldness, however, are equally common in the two conditions. Locus heterogeneity was demonstrated by failure to identify the myotonic muscular dystrophy mutation in 14 families with

facioscapulohumeral (FSH) muscular dystrophy in the distribution of limb weakness, especially the typical facioscapulohumeral appearance of the shoulder girdle. The two have been distinguished by lack of facial weakness, a slender reed for differential diagnosis. However, Wilhelmsen et all&dquo; found that the disorder mapped to chromosome 12 and not to the facioscapulohumeral locus on chromosome 4, so establishing this as a separate disorder. (In the process, they found that a family with both polyposis and facioscapulohumeral muscular dystrophy did map to chromosome 4

and, therefore, was really typical facioscapulohumeral muscular dystrophy.) Another debate about scapuloperoneal muscular dystrophy (SPMD), however, has not been resolved, namely whether there are neurogenic forms of facioscapulohumeral and scapuloperoneal syndromes. DeLong and Siddiquel3’ described a family with neurogenic features and they132 have now mapped it to chromosome 12, separated by a distance of 7 to 38 cM from the scapuloperoneal muscular dystrophy locus. In these syndromes, assignment of neurogenic or myopathic causation has been difficult because electromyography (EMG) and muscle biopsy patterns seem to vary in different members of a family. This issue will not be settled until the affected gene products are identified in these families. GENE MECHANISMS AND ALLELIC VARIATION

Expansion of Trinucleotide Repeats The first inherited disease to be associated with expansion of trinucleotide repeats was spinobulbar muscular atrophy (Kennedy-Alter-Sung disease). The list now includes Huntington disease, myotonic muscular dystrophy, spinocerebellar ataxias, Friedreich ataxia, Machado-Joseph syndrome, and others are sure to follow. Some are X-linked, others autosomal dominant or recessive. Some affect particular parts of the brain, some lower motor neurons, some primarily affect muscle. Some are pleiotropic (affecting other organs) with testicular failure, cataract, heart disease, or diabetes mellitus in a disproportionate number of patients. The phenotypic variation has been linked to the length of the expanded triplet repeat in the affected gene-the longer the repeat, the earlier the onset (anticipation) and the more severe the syndrome (potentiation). How this comes about in such different diseases is being unravelled at a rapid pace. In diseases as different as myotonic muscular dystrophy, 133 spinocerebellar ataxia, 134,135 and Huntington disease,136-1:38 studies of cultured tissue or transgenic mice 139 bearing the mutated gene imply that the clinical disorder results from a toxic gain of function of the gene product. In all of these conditions an expanded CAG repeat seems to

129

trap aberrant transcribed messenger RNA within the nucleus. It is not clear whether the pathogenesis of each disease results from decreased amounts of abnormal gene product, interference with neighboring genes, abnormal heterochromatin, or interactions of an abnormal gene product with different proteins necessary for cellular health. It is not clear whether the toxic gain of function results from the mutant protein or from the aberrant mRNA. In Huntington disease, the error results in the accumulation of scrapie prion-like deposits or Alzheimer-like aggregates. 140

Facioscapulohumeral Muscular Dystrophy and Position Effect

Variegation

Facioscapulohumeral muscular dystrophy is an inherited disorder, transmitted as an autosomal dominant trait. Sporadic cases are almost all due to new mutations at 4q35. However, about 10% of families do not map to this gene, implying locus heterogeneity. 141 One probe, p 13-11, detects deletions of multiple copies of a 3.2-kb tandem repeat, creating an abnormal small fragment with the restriction enzyme EcoRl. This probe was identified in a search for homeobox genes in Drosophila. It is thought that the 3.2-kb repeat contains the disease gene. Normally, there are 12 to 96 copies of the repeat; in patients with facioscapulohumeral muscular dystrophy there is a maximum of 8. In normal subjects, EcoRll produces fragments much larger than 28 kb, but facioscapulohumeral muscular dystrophy patients show fragments of 14 to 28 kb. The probes do not seem to encode a protein with any direct association to the disease, but there is a relation between the size of the deletion and age at onset. The disease may be due to &dquo;position effect variegation,&dquo; an indirect effect on a key gene at another locus There are no good gene candidates in the region, which maps close to the telomere and includes a 3.3-kb repeat family that is dispersed over heterochromatic regions of the genome. Position effect variegation could induce allele-specific transcriptional repression of a gene that becomes more centromeric as a result of the deletions. 143 This effect was first identified as a variable but heritable inhibition of euchromatic gene activity when juxtaposed with heterochromatin. Euchromatin contains most of the single-copy DNA and mutable genes, decondenses during interphase, and replicates throughout the S phase. Heterochromatin contains few mutable genes, is rich in repetitive sequences, and replicates late in the S phase.144 At least one other heritable human disease has been attributed to position effect variegation.145 This is yet another mechanism that can explain allelic variation and may explain why anticipation may be seen in facioscapulohumeral muscular dystrophy even though it is not related to a triplet repeat

expansion.

146

SUMMARY

Molecular genetics has introduced new concepts that have transformed clinical views of inherited diseases. Mechanisms unknown a decade ago now explain the diversity of clinical syndromes that map to the same gene locus. Both

locus heterogeneity and allelic heterogeneity show the relations between some syndromes first thought to be distinct, and the differences of syndromes thought to be identical. The identification of gene products partially explains the pathogenesis of syndromes and provides new views of normal structure and function. The discovery of dystrophin led to the discovery of &dquo;related&dquo; cytoskeletal proteins and then to a new understanding of limb-girdle muscular dystrophies. Recognition of the structure of PNP22 and P~ has led to new understanding about clinical variants of CharcotMarie-Tooth disease. For many diseases, DNA diagnosis or linkage now defines the clinical set and requires new clinical classifications and a new language. Isolation of the gene for a disease provides direct DNA diagnosis for affected individuals and for prenatal diagnosis. If there is no effective treatment for a disease, the possibility of presymptomatic diagnosis raises ethical questions. There are practical limits to a review like this. For instance, there is a rich literature on the variations of clinical syndromes due to deletions or point mutations of mitochondrial DNA, and we have not discussed all of the other potential forms of allelic variation listed in Table 1. We can anticipate more illumination of the causes we know and we can anticipate the arrival of causes we do not yet anticipate. What happens next can only be more illuminating. Clinical neurologists will participate in delineating the specific syndromes and assuring clinically useful nomenclature.

Acknowledgment This paper has been revised and updated from

an

earlier lecture. 147 I am indebted

colleagues, especially S. DiMauro, E. Schon, M. Hirano, D.C. DeVivo, T.C. Gilliam, T. Lynch, and K. Wilhelmsen for their patience in explaining modem genetto my

ics to

me.

They are not, however, responsible for any of my views.

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