Group of hereditary neurological disorders of the puppy characterised by deficient myelination of the central nervous system and, in some forms, of specific tracts of the spinal cord. They manifest as generalised tremor of early onset (10-12 days of life). Under the common name at least two distinct molecular forms are recognised: in the English springer spaniel it is due to a mutation in PLP1 (X-linked, the canine equivalent of Pelizaeus-Merzbacher disease); in the Weimaraner it is due to a mutation in FNIP2 (autosomal recessive). The prognosis differs: the Springer spaniel usually dies in the first months, whereas the Weimaraner improves with age.

Affected breeds: English springer spaniel (X-linked form, PLP1) and Weimaraner (autosomal recessive form, FNIP2). In the Weimaraner the carrier frequency was estimated at around 4.3 % in the initial series (9 carriers out of 105 Weimaraners analysed). An allelic form appears to occur in the Chow Chow. For the Springer spaniel no large series with carrier frequency have been published; consider 'limited data'. A second variant in PLP1 (c.92T>A, p.Leu31Gln) has recently been described in the English cocker spaniel.

- Generalised tremor of onset around 10-12 days of life (when starting to walk)\n- Abnormal muscle tone and posture, with difficulty walking and standing up\n- In Springer spaniel: severe picture, without improvement, with death usually between 3 and 4 months\n- In Weimaraner: picture of variable intensity, with progressive clinical improvement from 3-4 months; some retain a persistent fine tremor of the hind limbs\n- Heterozygous females in Springer spaniel (carriers of the X-linked mutation) may show mild transient tremor in the first stage, with a mosaic of myelination in the CNS\n- Peripheral nervous system normally myelinated in both forms

The 'shaking pup' of the Springer spaniel was described by Griffiths and colleagues in 1981 as a defect of central myelination with sex-linked recessive inheritance. In 1990, Nadon, Duncan and Hudson identified the causal mutation in the PLP1 gene (proteolipid protein 1), a missense substitution c.110A>C (p.His37Pro) that interrupts oligodendrocyte development; the canine model was used for decades as an equivalent of the human disease Pelizaeus-Merzbacher. Independently, Kornegay and colleagues described in 1987 a syndrome of hypomyelination with tremor in the Weimaraner, of autosomal recessive inheritance and with a unique pattern of preferential involvement of the ventrolateral columns of the spinal cord. The molecular basis was revealed by Pemberton and colleagues in 2014: after a GWAS in 84 Weimaraners and resequencing of all genes in the critical region, they identified a single-base deletion in exon 9 of FNIP2 (c.880delA, p.Ile294fs*296), which predicts a truncated protein. The carrier frequency in the breed was estimated at around 4.3 %. An identical form described in the Chow Chow appears to be allelic.

- Test the breeding females of Springer spaniel with the PLP1 test before mating; affected males must not breed, and carrier females should only be mated with free males (the female offspring intended for breeding must be tested)\n- Test Weimaraner breeding animals with the FNIP2 test before mating; do not mate two carriers: 25 % risk of affected homozygotes\n- An FNIP2 carrier may be mated with a free animal; the offspring intended for breeding must be tested and preferably the free ones selected, progressively replacing the carrier without narrowing the gene pool\n- In Weimaraner, since affected animals usually survive and improve, it should be remembered that an asymptomatic adult dog may have been affected during lactation: test before breeding\n- In the case of a puppy with early-onset tremor, refer to neurology, rule out other causes (metabolic, infectious, portosystemic) and request the PLP1/FNIP2 genetic test before any mating of the parents\n- Exclude from breeding affected homozygous (or hemizygous in the Springer) animals

Differential diagnosis with other causes of neonatal/juvenile tremor: hyperekplexia (startle rigidity), neonatal hypoglycaemia, canine herpesvirus encephalitis, congenital portosystemic shunt, distemper, congenital hydrocephalus, familial myoclonus of the Labrador and CKS dystonia. Magnetic resonance imaging may show diffuse hypomyelination; the CSF is usually normal. In Springer spaniel the prognosis is poor; in Weimaraner, better with symptomatic management and prevention of falls/trauma during the tremor period. Genetic confirmation is important because it determines the prognosis (lethal in PLP1 vs. improvement in FNIP2) and the breeding advice.

1. Nadon NL, Duncan ID, Hudson LD (1990). A point mutation in the proteolipid protein gene of the "shaking pup" interrupts oligodendrocyte development. Development 110(2):529-537. PMID: 1723945
2. Pemberton TJ et al. (2014). A mutation in the canine gene encoding folliculin-interacting protein 2 (FNIP2) associated with a unique disruption in spinal cord myelination. Glia 62(1):39-51. PMID: 24272703
3. OMIA:000770-9615. Tremor, X-linked in Canis lupus familiaris (dog).
4. OMIA:000526-9615. Hypomyelination of the central nervous system in Canis lupus familiaris (dog).