Progressive spinal muscular atrophy of infants and young children. By Frederick E. Batten, M.D., F.R.C.P. Brain 1911; 33: 433–463; with Congenital familial spinal muscular atrophies and their relation to amyotonia congenita. By Knud H. Krabbe M.D. [From the Children's Department of the University Hospital (Rigs-hospitalet), and the Nerve-Polyclinic of the University Hospital, Copenhagen]. Brain 1920; 43: 166–91; with Distal type of chronic spinal muscular atrophy. Clinical, electrophysiological and pathological studies. By J. G. McLeod and J. W. Prineas (From the Department of Medicine, University of Sydney, Sydney, N.S.W., Australia). Brain 1971; 94: 703–14; with Clinical and genetic study of chronic proximal spinal muscular atrophy. By Sarah Bundey and Robert E. Lovelace (From the Moore Clinic, Johns Hopkins Hospital, Baltimore, Maryland, and the Neurological Institute, Columbia Presbyterian Hospital, New York, N.Y. 10032). Brain 1975; 98: 455–72.

It is a rare issue of Brain that does not illustrate how genetic analysis increasingly supports the classification of neurological disease; with the complexities of allelic heterogeneity, cis and trans effects, heteroplasmy, epigenetics and phenocopy each making for complexity and subtlety in understanding how mutation and polymorphism underlie symptoms and signs in the mouse cage or in the clinic. Before the advent of molecular genetics, meticulous clinical and laboratory description defined disease. There followed the high season of eponym, acronym and summary description that subtended medical nosology. In turn, the classical ‘textbook’ conditions were sculpted out of much broader accounts based on primary features that we now know to be syndromic. Take, for example, mutations of DYNC1H1—a term that does not, of itself, give much away in terms of what the mouse or the patient experience. In fact, they have distal spinal muscular atrophy. In turn, that disorder emerged from the collective of Charcot–Marie–Tooth disease, later classified through careful clinical and laboratory characterizations into subtypes, some sharing abnormality confined to lower motor neurons. Spinal muscular atrophies became a focus of interest early in the 20th century. Once the conditions described by (Guido) Werdnig [(1844–1919): ‘Zwei frühinfantile hereditäre Fälle von progressiver Muskelatrophie unter dem Bilde der Dystrophie, aber auf neurotischer Grundlage’. Archiv fur Psychiatrie und Nervenkrank, 1891; 22: 437–80] and (Johann) Hoffman [(1857–1919); ‘Ueber chronische spinale Muskelatrophie im Kindesalter auf familiärer Basis’. Deutsche Zeitschrift fur Nervenheilkunde, 1891; 1: 95–120 and 1893; 3: 427–70] had served as a prototype, neurologists started to worry away at the similarities and differences seen amongst children and adults with wasting and weakness of the limbs. Inter alia, these patients were considered variously to have myopathy, amyotonia congenita or spinal muscular atrophy. Much of that debate was played out in the pages of this journal and associated with the work of Frederick (Eustace) Batten (1865–1918) writing from 1897 to 1912 [‘Hereditary form of progressive muscular atrophy with spinal lesion in young children’, by Dr C. E. Batten. Brain 1897; 20: 536–42; ‘A case of congenital spinal muscular atrophy (family type), and a case of hæmorrhage into the spinal cord at birth, giving similar symptoms’, by Dr C. E. Beevor (with Dr F. E. Batten). Brain 1902; 25: 85–108; ‘Case of progressive muscular atrophy of spinal origin in a girl aged 11 years; with autopsy’, by Herbert Morley Fletcher and Frederick E. Batten. Brain 1903; 26: 473–87; ‘Progressive spinal muscular atrophy of infants and young children’, by Frederick E. Batten. Brain 1911; 33: 433–63; and ‘Progressive spinal muscular atrophy of infants (Werdnig-Hoffmann type)’, by F. E. Batten and Gordon Holmes. Brain 1912; 35: 38–49].

Batten trained in medicine at Trinity College, Cambridge, and St Bartholomew’s Hospital, London, qualifying in 1891 and spending his career as general physician at the Hospital for Sick Children (Great Ormond Street), and as pathologist (from 1899) and physician (from 1901) to the National Hospital for the Paralysed and Epileptic, Queen Square, where he served as Dean from 1908 until his sudden death from haemorrhage following appendicectomy aged 53. With James Risien Russell (1863–1939) and James Collier (1870–1935), Batten gave the first detailed description of subacute combined degeneration of the spinal cord (‘Subacute combined degeneration of the spinal cord’, by J. S. Risien Russell, F. E. Batten and James Collier. Brain 1900; 23: 39–110) and a form of neurodegeneration in children now designated ‘Batten’s disease’ (‘Cerebral degeneration with symmetrical changes in the maculae in two members of a family’, by F. E. Batten. Transactions of the Ophthalmological Societies of the United Kingdom, 1902; 23: 386–90), also known as Spielmeyer-Vogt-Sjögren-Batten disease. As one of the first renowned paediatric neurologists, Batten contributed to the descriptions and understanding of muscular dystrophy, amyotonia congenita, poliomyelitis (on which was based his Lumleian lectures to the Royal College of Physicians, 1916), muscle spindles, and spinal muscular atrophy. Dr (Frederic John) Poynton (1869–1943) recalled Batten as:

[coming] from St.Barts., with the characteristic “aura”, but a most pleasant man … Med. Registrar before Still [Sir George Frederic Still (1868-1941)] … When on the staff he did fine work on infantile paralysis. I was his junior Physician. His death was a tragedy, he rang me up to say that he was going to have an operation and to look after his ward (Annie Zunz). I went to see him at the Nursing Home, to be told he had died of haemorrhage after the operation! His Ward Sister died some months after him from Influenza. He was a sad loss to us, for he was the youngest of the Senior Physicians, cut off in his prime. His notes on cases were a model of thoroughness, and many of them never were used by him for his life work on children.

Gordon Holmes (1876–1965) considered Batten to be honest, simple and direct—‘his geniality and enthusiasm made him a universal favourite’. In the measured terms of his biographer in the anonymous Queen Square and the National Hospital: 1860–1960 [known to be written by Macdonald Critchley (1900–97)] ‘Batten’s unexpected death … prematurely ended a career which promised to be fruitful, even brilliant’. In time, the highly specialized unit responsible for patients with acute poliomyelitis opened in 1952 at the National Hospital was named ‘The Batten Unit’.

In the issue of Brain for January 1898, Dr Batten writes a critical digest (vide supra) in which he summarizes six papers from other journals starting with those of Werdnig and Hoffman that describe ‘a form of muscular atrophy occurring in children which as yet has not obtained general recognition’. The pathological features are loss of anterior horn cells in the cervical and lumbar region; degeneration of the peripheral nerves; and atrophic muscles. But the seat of the primary pathology is not so clear. By 1911, Dr Batten can draw on the experience of several cases:

The occurrence of progressive paralysis and muscular atrophy due to a lesion of the lower motor neuron is a condition of some rarity both in infants and young children. During the past ten years I have seen some eight cases which may be placed under such a heading. Some of these have been under my own care, others under the care of my colleagues, but I have made the pathological examination in all cases in which an autopsy has been obtainable.

Taking care to exclude primary myopathies, including myotonia, poliomyelitis, spinal cord or root injury, congenital defects of the cord, the peroneal type of muscular atrophy (Charcot–Marie–Tooth disease), von Recklinghausen’s disease and the effects of spinal caries and spinal growth, his eight cases are exemplified by progressive muscular weakness, often familial, with onset during the first weeks or months of life that gradually progresses to end in death after a variable period of weeks, months, or years. Atrophy of the cells of the anterior horn is the constant pathological finding (Fig. 1). These cases correspond to those described by Werdnig and Hoffmann. But the literature is already becoming crowded and Dr Batten reflects that ‘the forms of myopathy which occur in young children become year by year more generally recognized’. His reading is that, of the many reports now available, only 13 are cases which, from their clinical symptoms with or without autopsy, may be considered as examples of the Werdnig-Hoffmann type. Over time cases not presenting until later in childhood, or even adult life, have been recognized and considered to be examples of spinal muscular atrophy not dissimilar to the infantile forms. This results in diagnostic confusion and the spurious merging of unrelated disorders having symptoms and signs in common. In particular, amyotonia congenita is a distinct disease of early childhood, characterized by an extreme degree of loss of tone and feebleness in all muscles of the body, but which may improve as the child ages and with the ability to perform all movements, albeit in a feeble manner, sometimes retained. Later, Knud Krabbe (1885–1961) emphasizes the difficulty in separating spinal muscular atrophy from amyotonia congenita and the primary muscular atrophies (‘Congenital familial spinal muscular atrophies and their relation to amyotonia congenita’. Brain 1920; 43: 166–91).

Figure 1

(A) Cells from the anterior horns of the cervical region, stained by the Nissl method, showing marked atrophy of cells, two normal cells alone remaining. (B) Cells from the lumbar region showing similar changes. Magnification 170 diameters. From Batten (1911).

Figure 1

(A) Cells from the anterior horns of the cervical region, stained by the Nissl method, showing marked atrophy of cells, two normal cells alone remaining. (B) Cells from the lumbar region showing similar changes. Magnification 170 diameters. From Batten (1911).

One analysis is that amyotonia congenita is a disorder of muscle with hypotonia and weakness, hyperflexibility of the joints, and atrophy of the anterior horn-cells and muscle fibres (Fig. 2). This is usually familial and conforms to Mendelian laws of inheritance but with certain conditions needed in order to determine its development, ‘reduced penetrance’ in modern terms. The other, and more likely interpretation, is that the diagnosis of ‘amyotonia congenita’ also embraces an illness characterized by hypotonia of the muscles, hyperflexibility of the joints and slight paresis, but not familial and without muscle atrophy that carries a comparatively good prognosis. Only a few such cases have come to autopsy. Evidently, Collier and Batten hold opposite views on this distinction. Collier sees many differences between cases of muscle weakness in childhood. He draws attention to the presence or not of a familial tendency; variable onset of the disease—congenital or appearing after an acute illness; the unpredictable clinical course—progressive or with spontaneous recovery; variations in the distribution of weakness and the tendency to affect new regions over time; and the presence, or not, of muscle wasting and absent tendon reflexes. Professor Krabbe reads much ambiguity into the writings of Batten and Beevor, who originally considered their cases to be congenital myopathies but, in discussions at the Royal Society of Medicine, subsequently declaring these to be examples of amyotonia congenita. Eventually Krabbe resolves the matter in his own mind by arguing for three distinct conditions. First is (Herman) Oppenheim’s (1858–1919) amyotonia congenita—often a benign disease characterized by hypotonia, hyperflexibility and weakness, but no atrophy: ‘if the patient does not die from intercurrent disease, it may be assumed that he is cured’. This is not familial and can be considered as a retarded development of the muscles. Second are cases of amyotonia congenita, rare in the literature, in which atrophy of the anterior horn cells and muscles is found at autopsy. Third is the condition, usually familial, described by Werdnig and Hoffmann, which also shows atrophy of the anterior horn cells and muscles, ‘demonstrable by X-rays’, and with a tendency for progression.

Figure 2

‘A case of congenital muscular weakness with hypotonia of the muscles and loss of the tendon reflexes. The clinical and post-mortem findings established the diagnosis: it was amyotonia congenita’. (A) Case 2. (B) Spinal cord, stained with Weigert-Kulschitzky-Wolters method. Shows the degeneration of the anterior roots. (C) Muscle stained with van Giesen-Hansen’s method, showing normal and atrophic muscle fibres and connective tissues. From Krabbe (1920).

Figure 2

‘A case of congenital muscular weakness with hypotonia of the muscles and loss of the tendon reflexes. The clinical and post-mortem findings established the diagnosis: it was amyotonia congenita’. (A) Case 2. (B) Spinal cord, stained with Weigert-Kulschitzky-Wolters method. Shows the degeneration of the anterior roots. (C) Muscle stained with van Giesen-Hansen’s method, showing normal and atrophic muscle fibres and connective tissues. From Krabbe (1920).

After this burst of activity, the pages of Brain are largely silent on spinal muscular atrophy until the 1970s, by which time events have moved on. Werdnig-Hoffmann disease now refers to the earliest clinical descriptions of childhood spinal muscular atrophy. The eponymous Kugelberg-Welander disease is named after Erik Klas Hendrik Kugelberg (1913–83) and Lisa Welander (1909–2001), who described cases with much later age at onset but distinguished these from examples of muscular dystrophy (invariably the first description is provided by others: ‘Hereditary proximal spinal muscular atrophy: a clinical entity simulating progressive muscular dystrophy’, by G. Wohlfart, J. Fex and S. Ellason. Acta Psychiatrica Scandinavica 1955; 30: 395–406; followed by ‘Heredofamilial juvenile muscular atrophy simulating muscular dystrophy’, by E. K. Kugelberg and L. Welander. Archives of Neurology and Psychiatry 1956; 75: 500–509). And an intermediate type of spinal muscular atrophy has been named after Victor Dubowitz, a paediatric neurologist working in the UK. Phenotypic varieties of the later onset conditions have been described, including those with facio-scapulo-humeral muscle weakness, scapulo-peroneal distribution and generalized muscle weakness. Now Professor James (‘Jim’) McLeod and Dr John Prineas draw attention to a different phenotype amongst the spinal muscular atrophies that takes us back to an earlier source of syndromic confusion.

The distal form of chronic spinal muscular atrophy is already recognized but rare. McLeod and Prineas describe six cases. PP, a boy aged 5 has delayed motor milestones so that, at presentation, he is unable to run, walk upstairs or rise from a sitting position. Examination confirms these abnormalities and shows distal wasting and weakness of the legs with pes planus deformity of the feet. The reflexes are preserved and sensation intact. RD, a man aged 23, has recently developed an unsteady gait and difficulty running. There is a family history affecting three generations. RD has distal wasting and weakness, especially of dorsiflexion and eversion, with absent ankle tendon reflexes but no foot deformity and with normal sensation. BE, a boy aged 11, with pes cavus at birth, shows slow motor milestones but can walk and run, with difficulty. He has generalized and petit mal epilepsy. His arms are abnormal and there is also both proximal and, more marked, distal weakness and wasting of the legs with preserved reflexes and sensation intact. At the age of 8, RS, a boy now aged 13 years, is observed to have an abnormal gait. Examination shows pes cavus and a lumbar lordosis; he has wasting and weakness of the intrinsic hand muscles and his legs below the knees, absent ankle jerks and normal sensation (Fig. 3). EO’K, aged 56, is well until her early 20s when she develops asymmetric progressive weakness of the legs so that she requires a stick to walk and cannot easily negotiate stairs or an incline. There is a family history in three generations. She has wasting and weakness below the knees with absent lower limb tendon reflexes and normal sensation. Her daughter, CP, aged 30, has a recent history of weakness in the legs which has progressed so that she now cannot stand on her toes or run, and has cramps in the calves. She also has wasting and weakness below the knees with absent lower limb tendon reflexes and normal sensation. Neither mother nor daughter have foot deformities. The authors’ interest lies primarily in the electrophysiological and histological features of their cases. The evidence for chronic partial denervation of the tibialis anterior muscles, sometimes more extensive and involving the calf and quadriceps muscles and the intrinsic hand muscles, with normal motor conduction velocities and sensory action potentials, is apparent in all six cases. The appearance of the sural nerve, biopsied in four patients, under light microscopy is normal. There is no evidence for demyelination or abnormality of teased fibres and no irregularities of the thickness of myelin or intermodal lengths to suggest regeneration and remyelination. Three nerves are also studied using electron microscopy but everything is considered normal. Muscle biopsy shows evidence for neurogenic atrophy with small angulated fibres, some of which have chains of abnormal sarcolemmal nuclei (Fig. 4). Taken together, the clinical and laboratory evidence indicates disease of the anterior horn cells, or possibly the motor nerve roots. In discussion Jim Mcleod and John Prineas rehearse the seminal publications of Werdnig and Hoffmann, and Kugelberg and Welander from 1891/1893 and 1956, respectively, and the recognition that a distal form of spinal muscular atrophy may be seen, as described by Peter Dyck and Ed Lambert [(1915–2003): ‘Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. I. Neurologic, genetic, and electrophysiologic findings in hereditary polyneuropathies. II. Neurologic, genetic, and electrophysiologic findings in various neuronal degenerations’. Archives of Neurology, Chicago, 1968; 18: 603–18 and 619–25). Their own cases are similar with onset in the distal musculature of the legs in childhood or early adult life, often familial, sometimes also involving the hands but distinct from those described by John Meadows and David Marsden (1938–98) in which the upper limbs are first affected and the inheritance pattern more likely autosomal recessive. Distal spinal muscular atrophy resembles Charcot–Marie–Tooth disease in the distribution of muscle wasting and in its course. Peter Dyck has suggested that Charcot–Marie–Tooth disease consists of three types: hypertrophic neuropathy with segmental demyelination and remyelination; primary axonal degeneration; and a disorder of anterior horn cells. The contribution of McLeod and Prineas is to separate cases that might otherwise be classified as hereditary motor neuropathy and to confirm the distinction between the latter two variants of Charcot–Marie–Tooth disease based on their demonstration of normal sural nerve histology in the present series.

Figure 3

R.S., a boy aged 13. Distal wasting of the legs with pes cavus. From McLeod and Prineas (1971).

Figure 3

R.S., a boy aged 13. Distal wasting of the legs with pes cavus. From McLeod and Prineas (1971).

Figure 4

(A) Electron micrograph of sural nerve. Myelinated and unmyelinated fibres appear normal, ×3870. (B) Tibialis anterior muscle. Groups of fibres are markedly atrophic with chains of sarcolemmal nuclei. Longitudinal section. Haematoxylin and eosin. ×400. From McLeod and Prineas (1971).

Figure 4

(A) Electron micrograph of sural nerve. Myelinated and unmyelinated fibres appear normal, ×3870. (B) Tibialis anterior muscle. Groups of fibres are markedly atrophic with chains of sarcolemmal nuclei. Longitudinal section. Haematoxylin and eosin. ×400. From McLeod and Prineas (1971).

Four years later, Sarah Bundey (1936–98) and Robert Lovelace consider genetic aspects in cases of spinal muscular atrophy with proximal muscle involvement surviving beyond the normal life expectancy of Werdnig-Hoffmann disease and designated as the intermediate form of Dubowitz or as Kugelberg-Welander disease. Whilst the existing pedigrees mainly suggest recessive conditions, a few examples of autosomal dominant and sex-linked inheritance are also described; and too many cases are sporadic for anything definitive to be said concerning the genetics of more chronic forms of spinal muscular atrophy. For operational purposes, in their series ‘chronic’ means disease duration of six or more years in individuals alive at 10 years or older and in whom the syndrome is confined to lower motor neurons with a neurogenic pattern on electromyography, and muscle pathology consistent with denervation. Sixty-nine cases are identified from centres or neurologists practising in the eastern USA. Taking the 19 examples contributed by the Neurological Institute of New York, over the same period 90 infants have been diagnosed with Werdnig-Hoffmann disease and 47 with the Kugelberg-Welander variant of spinal muscular atrophy. Of the 69 cases, 38 are available for study and considered to have spinal muscular atrophy although five are atypical in one respect or another and not considered further. Of note is that six of those already excluded on clinical grounds fail to meet the entry criteria because of predominantly distal involvement at onset. One hundred and forty-eight of 189 living relatives are contacted and examined of whom 18 are affected; all but two are examined by electromyography and/or muscle biopsy. Onset in the 33 cases is with a waddling gait on starting to walk usually before the age of 2; some have more generalized weakness and all show progression to involve both the pelvic and shoulder girdles. These children often have fasciculations and deformities of the feet and spinal column. Prognosis for remaining ambulant is inversely related to age at onset with no case manifesting in infancy still walking at 10 years; and, conversely, no late-onset individual is off his or her legs by that age (Fig. 5). Electrophysiological studies are consistent with the criteria for partial denervation and, with rare exceptions, show normal motor and sensory nerve conduction velocities. Muscle biopsies prove less helpful and with findings that often conflict with the clinical and electrophysiological data: 16 are consistent with mixed nerve and muscle disease or a primary muscle disorder; and only 6 of 22 biopsies show the expected changes of chronic partial denervation. Furthermore, more than 50% of the patients have a modest increase in serum creatine phosphokinase and this is especially obvious in those with myopathic changes on biopsy.

Figure 5

Ages of onset in 32 index patients with onset by 10 years, related to their disability at 10 years. From Bundey and Lovelace (1975).

Figure 5

Ages of onset in 32 index patients with onset by 10 years, related to their disability at 10 years. From Bundey and Lovelace (1975).

In the 19 patients with early onset, 12 of 57 siblings are also affected—the age at onset and phenotype proving relatively similar within families. Rarely the index cases also have children of their own; but no one of these is affected and the progeny of the index cases’ normal siblings are also normal. Conversely, only 2 amongst 29 siblings of index cases aged >2 years at onset are also affected, as is one son, although 13 siblings remain below the age at which the disease might yet manifest. All three affected first degree relatives (the two siblings and one child) have severe disease mimicking the phenotype of their first degree relative but with younger age at onset; as is also the case for two second degree affected relatives, one the product of a consanguineous marriage.

Does any consensus emerge from this heterogenous group of cases defined on the basis of proximal muscle weakness with onset in childhood and electrophysiological evidence for denervation, not infrequently in the context of histology showing myopathy, and a raised creatine phosphokinase? Clearly, ascertainment is incomplete with only a minority of cases identified from each source. The modern reader will inevitably offer specifically different diagnoses for some of the atypical cases—such as those with marked contractures or severe ophthalmoplegia. But some interpretation of the core cohort of 33 cases can be proposed given the higher familial recurrence in early onset cases. The involvement of siblings suggests an autosomal recessive pattern of inheritance in most; but at least one pedigree indicates dominant inheritance, and with additional cases explained by sporadic mutation. Conversely, in older onset cases, despite the low recurrence rate overall, there do appear to be some autosomal recessive cases—showing anticipation of the clinical phenotype—and at least one example of dominant inheritance, the second affected having predominantly distal muscle wasting and weakness. As for the remainder, Sarah Bundey and Robert Lovelace discount sporadic mutations and conclude that causes other than genetic may be responsible for spinal muscular atrophy in at least 50% of cases. Thus the dichotomy between familial and acquired cases argued by the early commentators persists.

Against this background, in the present issue Majid Hafezparast and colleagues use mice with mutations in the gene encoding the heavy chain subunit of the cargo binding domain of dynein (Dync1h1), resulting in distal spinal muscular atrophy with intellectual disability, to show abnormalities in motor proteins that slow up the movement of endosomes towards the nucleus and accelerate their trafficking towards the periphery; and they speculate on the consequences for underlying signalling events that might contribute to the neuropathology and phenotype of DYNC1H1 mutations (see page 1883).